J Gastroenterol (2018) 53:1048–1064 https://doi.org/10.1007/s00535-018-1480-0 ORI G INAL ARTI CL E—ALIMENTARY T R ACT Systematic review with meta-analysis: real-world effectiveness and safety of vedolizumab in patients with inﬂammatory bowel disease 1 2 3 4 • • • • Stefan Schreiber Axel Dignass Laurent Peyrin-Biroulet Greg Hather 5 6 5 5 • • • • Dirk Demuth Mahmoud Mosli Rebecca Curtis Javaria Mona Khalid Edward Vincent Loftus Jr. Received: 23 May 2018 / Accepted: 24 May 2018 / Published online: 4 June 2018 The Author(s) 2018 Abstract 2014–June 22, 2017. Response and remission rates were Background Selective patient recruitment can produce combined in random-effects meta-analyses. discrepancies between clinical trial results and real-world Results At treatment week 14, 32% of UC patients [95% effectiveness. conﬁdence interval (CI) 27–39%] and 30% of CD patients Methods A systematic literature review and meta-analysis (95% CI 25–34%) were in remission; and at month 12, were conducted to assess vedolizumab real-world effec- 46% for UC (95% CI 37–56%) and 30% for CD (95% CI tiveness and safety in patients with ulcerative colitis (UC) 20–42%). For UC, the rates of corticosteroid-free remission or Crohn’s disease (CD). MEDLINE, MEDLINE In-Pro- were 26% at week 14 (95% CI 20–34%) and 42% at month cess, EMBASE, and Cochrane databases were searched for 12 (95% CI 31–53%); for CD they were 25% at week 14 real-world studies of vedolizumab in adult patients with (95%, CI 20–31%) and 31% at month 12 (95%, CI UC/CD reporting clinical response, remission, corticos- 20–45%). At month 12, 33–77% of UC and 6–63% of CD teroid-free remission, UC/CD-related surgery or hospital- patients had mucosal healing. Nine percent of patients ization, mucosal healing, or safety published from May 1, reported serious adverse events. Conclusions Vedolizumab demonstrated real-world effec- tiveness in patients with moderate-to-severely active UC or CD, with approximately one-half and one-third of patients, This study was previously presented as a poster at the 2016 Advances respectively, in remission at treatment month 12. These in Inﬂammatory Bowel Diseases Congress (AIBD) and the 2017 ﬁndings are consistent with clinical trial data and support European Crohn’s and Colitis Organisation Congress (ECCO). the long-term beneﬁt–risk proﬁle of vedolizumab. Rebecca Curtis was an employee of Takeda at the time of manuscript development. Keywords Vedolizumab Inﬂammatory bowel disease Ulcerative colitis Crohn’s disease Real-world Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00535-018-1480-0) contains supple- effectiveness mentary material, which is available to authorized users. & Stefan Schreiber Takeda Oncology, Takeda Global Research and firstname.lastname@example.org Development, Boston, MA, USA Global Medical Affairs, Takeda International-UK Branch, Department of Internal Medicine I and Institute of Clinical London, UK Molecular Biology, University-Hospital Schleswig-Holstein, Christian-Albrechts-University, Rosalind-Franklin-Strasse Department of Medicine, King Abdulaziz University, Jeddah, 12, 24105 Kiel, Germany Saudi Arabia 2 7 Department of Medicine 1, Agaplesion Markus Hospital, Department of Gastroenterology and Hepatology, Mayo Goethe University, Frankfurt, Germany Clinic College of Medicine, Rochester, MN, USA Inserm U954 and Gastroenterology Department, Nancy University Hospital, Lorraine University, Vandoeuvre-le `s-Nancy, France 123 J Gastroenterol (2018) 53:1048–1064 1049 monitoring is essential. Real-world data from large cohorts Introduction can further characterize a drug’s safety proﬁle not fully Current treatment options for inﬂammatory bowel diseases elucidated in clinical trials [16, 17]. We sought to sys- tematically review and summarize published literature on (IBD) include aminosalicylates, corticosteroids (CS), thiopurines, calcineurin inhibitors, anti-cytokines, and anti- real-world effectiveness and safety of vedolizumab studies and conduct a meta-analysis of effectiveness data. integrins [1, 2]. Vedolizumab is a gut-selective, human- ized, monoclonal antibody that binds to a b integrins, 4 7 selectively blocking gut-selective lymphocyte trafﬁcking [3, 4]. Vedolizumab efﬁcacy and safety in moderate-to- Materials and methods severely active ulcerative colitis (UC) and Crohn’s disease Study selection (CD) were established by the GEMINI clinical trials [5–7], with marketing approval granted in May 2014 in the USA A systematic review of MEDLINE, MEDLINE In-Process, and later in Europe [8, 9]. Clinical guidelines recommend vedolizumab for UC not previously treated with biologic EMBASE and Cochrane (May 1, 2014–June 22, 2017), and searches of clinicaltrials.gov and the World Health Orga- therapy , and for UC or CD that is refractory to con- ventional or anti-tumor necrosis factor-alpha (TNFa) nization International Clinical Trials Registry Platform were completed. Conference proceedings from 2015 to treatment [1, 2]. Strict inclusion criteria used in randomized controlled June 2017 were searched. Two researchers reviewed rele- vant publications independently, with disagreements trials (RCTs) can limit the patient population and gener- resolved by discussion or a third reviewer. Studies were alizability of trial results to clinical practice, with the latter eligible if they included real-world evidence (e.g., medical further compromised by IBD patient heterogeneity record review, database, registry) and an adult patient [11, 12]. Indeed, up to two-thirds of patients with IBD population (C 18 years when initiating vedolizumab) might be ineligible to participate in RCTs of biologics receiving vedolizumab (Takeda Pharmaceuticals Interna- [11, 13]. An additional hindrance is the increasing unwillingness of patients to accept placebo control. Ran- tional, Inc., Deerﬁeld, IL) for IBD (UC, CD, or unspeciﬁed/ indeterminate colitis) and if outcomes reported were of domized controlled trials are, therefore, unlikely to fully represent the real-world IBD population. However, physi- interest. English and non-English language studies were eligible for inclusion. Studies were excluded if the total cians require real-world effectiveness data to complement clinical trial results and inform treatment decisions. patient population was \ 10, if vedolizumab was used off- label, or if safety data were reported at event level only (no Assessing the treatment quality and effect size in clinical practice and evaluating the strength of this evidence denominator). Investigators were contacted for unpub- lished data (unpublished clinical data provided courtesy of through systematic literature reviews and meta-analyses Dr. Mark A. Samaan and Dr. Peter Irving from their UK can provide such data. Summation can overcome potential bias associated with individual studies and address chal- study, 2016) and conference abstracts, and manual back- ward citation tracking of references (including studies) lenges associated with the transferability of RCT ﬁndings; systematic literature reviews are, therefore, at the top of the were performed to identify additional relevant studies [18–22]. evidence hierarchy as deﬁned by the Oxford Centre for Evidence-Based Medicine [14, 15]. Data extraction and outcome measures Data from the GEMINI 3 trial suggest that the full effect of vedolizumab-induced clinical remission in patients with One researcher used predeﬁned parameters to extract all CD may not be apparent before treatment week 10 . The data using a piloted form and, after this, a second European Summary of Product Characteristics and US researcher performed data checks for accuracy. Informa- Prescribing Information both recommend that vedolizumab tion obtained for each eligible study included author, year treatment of UC and CD should be discontinued if a therapeutic beneﬁt is not observed by week 14 (by week 10 of publication, geographic location, and clinical outcomes reported. Patient characteristics included disease duration, in UC in Europe) [8, 9]. Real-world data allow evaluation of the optimal time points for assessing clinical effective- age, sex, prior medication history, and IBD-related surg- eries. The primary outcome measure was clinical remis- ness and when concomitant therapies should be adjusted based on therapeutic response outside of RCT protocol- sion; secondary outcome measures were clinical response, CS-free clinical remission, mucosal healing, endoscopic deﬁned assessments. Given that vedolizumab is relatively new and the improvement, surgery and hospitalization rates, dose- escalation rates, and safety. Clinical response, clinical number of treated patients is increasing, ongoing safety remission, and CS-free clinical remission rates (classiﬁed 123 1050 J Gastroenterol (2018) 53:1048–1064 according to summarized measures in Table S1) (Samaan Results and Irving, 2016) [13, 23–48] were collected at weeks 6, 14, 26–30 (month 6), and 46–54 (month 12), where Study and patient characteristics available. Subanalyses were performed to determine clin- ical remission rates by geographic region and in patients Of 1542 publications identiﬁed, 89 publications (N = 9486; who were anti-TNFa-naive. n = 4532 CD; n = 3216 UC; n = 1738 IBD unspeciﬁed/ indeterminate/other) were eligible to be included in this review (Figure S1). Eleven studies (n = 1692) did not Grading of evidence report separate UC and CD rates [18, 20, 22, 53–60]. Six studies focused on CD, 5 focused on UC, and 61 examined Studies were assessed using the Oxford Centre for Evi- both conditions. Eighteen studies were full-text articles and dence-Based Medicine 2011 Levels of Evidence, which 73 were conference proceedings. Most studies  were evaluates the strength of evidence (including quality and conducted in the USA, followed by Europe . The bias) based on study design [15, 49]. One reviewer grading of quality of evidence of the studies (Table S2) appraised each study and assigned a level from 1 (high [15, 49] ranged from 3 (12 publications) to 4 (77 publi- quality or low risk of bias) to 5 (low quality or high risk of cations; Table S3) (Samaan and Irving 2016) bias) (Table S2) [15, 49], with uncertainty resolved by [13, 18, 20, 22–48, 53–110]. discussion with a second reviewer. The meta-analysis included 21 studies reporting clinical response (n = 2310) and 23 reporting clinical remission rates (n = 2298) (18 studies included an analyses of both Statistical analyses outcomes; Table S1) (Samaan and Irving, 2016) [13, 23–34, 36–48]. Ten studies reported CS-free clinical Meta-analyses were performed to combine clinical remission rates (Table S1) (Samaan and Irving, 2016) response, clinical remission, and CS-free clinical remis- [13, 23, 24, 28, 29, 31, 36, 38, 42, 46] and 10 reported sion rates using R statistical software (version 3.2.2; R mucosal healing or endoscopic improvement (Fig. 5; Fig- Foundation; Vienna, Austria) with the ‘‘meta’’ package ure S2) [34, 40, 60, 69]. Of 46 studies reporting safety (version 4.3-2). When multiple publications were avail- outcomes, most were for UC/CD combined, rather than by able for a study, data from the most recent cohort were separate indication (Table S4) [13, 18, 20, 24, 26, 27, used for the combined analyses. Weighted mean clinical 31, 32, 37, 38, 40–42, 44–46, 53, 55, 56, 58, 59, 61, 64–68, response, clinical remission, and CS-free clinical remis- 70–74, 78–80, 84, 89, 91–95, 97, 98, 102, 104–109]. sion rates and corresponding 95% conﬁdence intervals Patient demographics are described in Table S3 (Sa- (CIs) were calculated using the DerSimonian–Laird ran- maan and Irving, 2016) [13, 18, 20, 22–48, 53–110]. The dom-effects model to account for between-study hetero- mean patient age was 40.9 years (range 34.3–67.1; 39 geneity . Where mean/median values and 95% CIs studies); the mean disease duration was 9.8 years (range were reported, data were used as stated (calculated using 2.9–18; 22 studies); and the mean percentage of patients the binomial distribution if 95% CIs were not reported). with prior anti-TNFa therapy was 80.4% (range 0–100%; For studies reporting safety, IBD-related surgery or hos- 42 studies). pitalization, and dose escalation, the proportion of events was calculated. For mucosal healing or endoscopic Primary outcome improvement, analyses were based on either a cumulative incidence approach or as a proportion of those receiving Clinical remission endoscopy. Study heterogeneity was determined using the I statistic Clinical remission was assessed in 18 studies in UC, 18 in (which describes the variability in the effect estimate that CD, and 13 in both populations (Table S1) (Samaan and results from heterogeneity rather than sampling error ) Irving, 2016) [13, 23–25, 27–34, 36, 38–40, 42–48]. In UC, and the Q-statistic (P \ 0.05 was considered signiﬁcant clinical remission was achieved in 24% of patients at week and suggested statistical heterogeneity). When C 10 stud- 6 (95% CI 13–41%) and 32% at week 14 (95% CI ies reporting the same outcome were available, publication 27–39%), which increased to 39% at 6 months (95% CI bias was assessed using Egger’s weighted regression 30–48%) and 46% at 12 months (95% CI 37–56%) (Fig. 1) statistic, with P \ 0.05 suggesting a higher likelihood of (Samaan and Irving, 2016) [13, 24, 25, 27– bias . 30, 32–34, 36, 38–40, 42, 65, 86]. In CD, clinical remission was achieved in 24% of patients at week 6 (95% CI 123 J Gastroenterol (2018) 53:1048–1064 1051 Study Patients Patients Week 6 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 39 121 32 (24–41) Baumgart et al. 13 115 11 (6–19) Mankongpaisarnrung et al. 5 7 71 (29–96) Shelton et al. 60 4 15 (6–30) Ungar et al. 65 2 24 (9–45) Random-effects model 24 (13–41) Heterogeneity: P < .0001 020 40 60 80 100 Study Patients Patients Week 14 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 47 121 39 (30–48) Baumgart et al. 27 115 23 (16–32) Chaparro et al. 13 42 31 (18–47) Christensen et al. 80 2 40 (19–64) Kopylov et al. 20 39 27 (17–39) Samaan et al. 78 1 39 (17–64) Shelton et al. 17 58 29 (18–43) Vivio et al. 85 1 53 (27–79) Random-effects model 32 (27–39) Heterogeneity: P = .13 0 20406080 100 Study Patients Patients Month 6 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 51 121 42 (33–51) Dulai et al. 67 180 37 (30–45) Hoog et al. 86 1 50 (25–75) Samaan et al. 50 1 50 (19–81) Stallmach et al. 11 60 18 (10–30) Zezos et al. 28 57 49 (36–63) Random-effects model 39 (30–48) Heterogeneity: P =.01 0 20406080 100 Study Patients Patients Month 12 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 51 121 42 (33–51) Dulai et al. 92 180 51 (44–59) Eriksson et al. 25 39 64 (47–79) Lenti et al. 16 36 44 (28–62) Pauwels et al. 36 50 (12–88) Samaan et al. 7 12 58 (28–85) Stallmach et al. 15 60 25 (15–38) Random-effects model 46 (37–56) Heterogeneity: P < .01 0 20406080 100 123 1052 J Gastroenterol (2018) 53:1048–1064 b Fig. 1 Meta-analysis of clinical remission rates among patients with was achieved in 14% at week 6 (95% CI 6–32%), 26% at ulcerative colitis receiving vedolizumab at the time points: a week 6; week 14 (95% CI 20–34%), and 32% at 6 months (95% CI b week 14; c 6 months; and d 12 months. The size of each square 21–45%), with the rate increasing to 42% at 12 months represents the weight assigned to each study based on sample size. (95% CI 31–53%) (Fig. 3) (Samaan and Irving, 2016) Error bars represent 95% CIs. Diamonds represent the point estimate of the averaged study rates; the lateral tips of the diamonds represent [13, 24, 28, 29, 35, 36, 38, 42, 65, 86]. 95% CIs. CI conﬁdence interval. Data from Amiot et al. , In CD, CS-free clinical remission was achieved by 13% Baumgart et al. , Mankongpaisarnrung et al. , Shelton et al. at week 6 (95% CI 8–21%), 25% at week 14 (95% CI , Ungar et al. , Chaparro et al. , Christensen et al.  20–31%), and 22% at 6 months (95% CI 15–32%) and was Kopylov et al. , Samaan et al. , Vivio et al. , Dulai et al. , Hoog et al. , Stallmach et al. , Zezos et al. , Eriksson maintained at 31% to 12 months (95% CI 20–45%) et al. , Lenti et al. , Pauwels et al. , Samaan et al. . (Fig. 4) (Samaan and Irving, 2016) Unpublished clinical data provided courtesy of Dr. Mark A. Samaan [13, 23, 24, 29, 36, 38, 46, 86]. Between-study hetero- and Dr. Peter Irving from their UK study, 2016 geneity was evident for all groups included in UC CS-free clinical remission analyses (P B 0.03 for all) and for all groups in the CD CS-free clinical remission analyses, other 20–27%), 30% at week 14 (95% CI 25–34%), 26% at than week 14 (P = 0.14). Corticosteroid-free response 6 months (95% CI 19–35%), and 30% at 12 months (95% results are summarized in Table S5. CI 20–42%) (Fig. 2) (Samaan and Irving, 2016) [13, 23–25, 27, 29, 30, 32, 34, 36, 38, 39, 43–48, 86]. Mucosal healing and endoscopic improvement Between-study heterogeneity was evident for all groups included in UC and CD remission analyses (I = 38–84%). Twelve studies reported mucosal healing (Fig. 5) However, Egger’s weighted regression for CD at week 14 [23, 26, 28, 34, 35, 40, 46, 47, 69, 77, 83, 103], and 4 indicated no publication bias (Egger’s P = 0.16). studies reported endoscopic improvement (Figure S2) [34, 40, 60, 69]. Mucosal healing rates ranged from 24 to Secondary outcomes 55% in patients with UC and 19–30% in patients with CD at month 6. At month 12, mucosal healing rates ranged Clinical response from 33 to 77% in patients with UC and 6–63% in patients with CD. In a study of patients with UC or CD, endoscopic Clinical response was evaluated in 16 studies in UC (Sa- improvement was observed in 76 and 52% of patients, maan and Irving, 2016) [13, 23–32, 34, 36–38, 41] and 20 respectively, at a median time point of 22 weeks (Fig- in CD [23–27, 29–32, 34, 36–38, 41, 43–47] (Table S1) ure S2) . In patients with CD, rates of endoscopic (Samaan and Irving, 2016) [13, 23–38, 41, 43–47]. Com- improvement were consistent over time with 53 and 50% bined clinical response rates in UC were 43% at week 6 of patients experiencing an improvement at week 16 and (95% CI 38–49%), 56% at week 14 (95% CI 50–62%), and week 52, respectively (Figure S2) . 52% at 12 months (95% CI 37–65%) (Table S5). In CD, the combined clinical response rate was 56% at week 6 IBD-related surgery and hospitalization rates (95% CI 46–65%), 58% at week 14 (95% CI 51–64%), and 40% at 12 months (95% CI 29–52%). Ulcerative colitis Three real-world IBD studies [62, 99, 110] included in our studies showed low to moderate between-study hetero- systematic review (Table S6) [13, 22, 23, 26, 31, geneity, except for those included in the 12-month response 35, 36, 40–42, 44–46, 54–56, 62–64, 67, 69, 71, 74, 76, rate analysis (I = 85%; P \ 0.001) and week 6 remission 80–82, 85–88, 90, 91, 93, 96–102, 110] demonstrated rate analysis (I = 82%; P \ 0.01). For CD, between-study reductions in hospitalization rates in the post-treatment heterogeneity was evident for all analyses (P \ 0.01 for versus pre-treatment period. all), with an I of 43–84%, suggesting moderate to high between-study heterogeneity. Vedolizumab dose-escalation rates Corticosteroid-free clinical remission Rates of vedolizumab dose escalation ranging from 4 to 60% up to week 54 were reported in 8 real-world studies Corticosteroid-free clinical remission was assessed in 9 (Table S7) [23, 33, 37, 41, 46, 57, 75, 108]. Dose-escala- studies in UC (Samaan and Irving, 2016) tion rates were lower in biologic-naive (4–20%) versus [13, 23, 24, 28, 29, 31, 36, 38, 42] and 8 in CD (Samaan biologic-experienced patients (6–29%) [57, 75]. Among 4 and Irving, 2016) [13, 23, 24, 29, 31, 36, 38, 46](8 studies reporting dose-escalation outcomes, 31–81% of reported both UC and CD CS-free clinical remission; patients recaptured response (Table S7) [33, 37, 46, 108]. Table S1). In patients with UC, CS-free clinical remission 123 J Gastroenterol (2018) 53:1048–1064 1053 Study Patients Patients Week 6 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 54 173 31 (24–39) Baumgart et al. 16 97 16 (10–25) Dulai et al. 23 212 11 (7–16) Gils et al. 87 2 30 (14–50) Shelton et al. 15 42 36 (22–52) Ungar et al. 14 47 30 (17–45) Random-effects model 24 (20–27) Heterogeneity: P < .01 0 20406080 100 Study Patients Patients Week 14 remission rate (%) Rate (%) 95% CI in remission assessed Abramowitz et al. 11 30 37 (20–56) Amiot et al. 63 173 36 (29–44) Baumgart et al. 23 97 24 (16–33) Blum et al. 42 2 18 (5–40) Chaparro et al. 10 53 19 (9–32) Christensen et al. 10 26 38 (20–59) Glover et al. 79 3 18 (8–34) Kopylov et al. 45 130 35 (26–43) Samaan et al. 7 19 37 (16–62) Shelton et al. 21 88 24 (15–34) Vos et al. 27 79 34 (24–46) Random-effects model 30 (25–34) Heterogeneity: P = .06 0 20406080 100 Study Patients Patients Month 6 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 55 173 32 (25–39) Blum et al. 5 16 31 (11–59) Dulai et al. 38 212 18 (13–24) Hoog et al. 77 2 26 (11–46) Samaan et al. 50 1 50 (19–81) Stallmach et al. 13 67 19 (11–31) Random-effects model 26 (19–35) Heterogeneity: P = .01 0 20406080 100 Study Patients Patients Month 12 remission rate (%) Rate (%) 95% CI in remission assessed Amiot et al. 52 173 30 (23–37) Dulai et al. 74 212 35 (29–42) Eriksson et al. 40 1 60 (48–72) Lenti et al. 68 4 12 (5–25) Pauwels et al. 17 1 6 (0–29) Samaan et al. 4 10 40 (12–74) Stallmach et al. 14 67 21 (12–33) Random-effects model 30 (20–42) Heterogeneity: P < .01 0 20406080 100 123 1054 J Gastroenterol (2018) 53:1048–1064 b Fig. 2 Meta-analysis of clinical remission rates among patients with Effectiveness in biologic-naive patients Crohn’s disease receiving vedolizumab at the time points: a week 6; b week 14; c 6 months; and d 12 months. The size of each square In biologic-naive patients with UC, clinical remission was represents the weight assigned to each study based on sample size. achieved in 51% of patients at week 14 (95% CI 40–62%) Error bars represent 95% CIs. Diamonds represent the point estimate of the averaged study rates; the lateral tips of the diamonds represent and 61% of patients at 12 months (95% CI 48–72%) 95% CIs. CI conﬁdence interval. Data from Amiot et al. , (Figure S3) [24, 28, 31, 36, 38]. In biologic-naive patients Baumgart et al. , Dulai et al. , Gils et al. , Shelton et al. with CD, clinical remission was achieved in 48% of , Ungar et al. , Abramowitz et al. , Blum et al. , patients at week 14 (95% CI 28–68%) and 44% of patients Chaparro et al. , Christensen et al. , Glover et al. , Kopylov et al. , Samaan et al. , De Vos et al. , Hoog et al. at 12 months (95% CI 18–75%) (Figure S4) , Stallmach et al. , Eriksson et al. , Lenti et al. , [24, 31, 36, 38]. a a Pauwels et al. , Samaan et al. . Unpublished clinical data provided courtesy of Dr. Mark A. Samaan and Dr. Peter Irving from their UK study, 2016 Discussion To the best of our knowledge, to date this is the most Vedolizumab safety comprehensive meta-analysis of real-world clinical response and remission rates for vedolizumab over Safety outcomes were reported in 46 studies (Table S4) 12 months of treatment, incorporating data from both peer- [13, 18, 20, 26, 27, 31, 32, 37, 38, 41, 42, 45, 46, 55, 56, 59, reviewed full-text manuscripts and abstracts. Real-world 61, 64, 65, 68, 70–74, 78–80, 84, 89, 94, 97, 102, 104, 105, effectiveness data provide valuable evidence to support the 107, 109] over a vedolizumab exposure/follow-up period efﬁcacy observed in RCTs, because trial patients may not of 0.5–12 months (exposure/follow-up data available for be representative of the real-world IBD population . 27 studies). Overall adverse event (AE) rates were reported In UC, clinical remission was achieved in approximately in 23 studies (0–67% of patients; n = 2358) and infections one-third of patients at 14 weeks and in approximately in 12 studies (range 5–24%; n = 1176). Serious AEs (range one-half of patients at 12 months. In CD, clinical remission 0–13%) were reported in 4 studies (n = 857), and serious was achieved by approximately one-third of patients at infections (range 4–10%) were reported in 3 studies both 14 weeks and 12 months. An important treatment (n = 832). Postoperative AEs were reported in 4 studies goal in the management of patients with IBD is the (range 8–65%) and serious postoperative AEs in 1 study achievement and maintenance of sustained CS-free clinical (43%). The most common AEs were upper respiratory tract remission [1, 2, 111]. Approximately, one-quarter of infections including nasopharyngitis (range 1–21%), patients with UC or CD achieved CS-free clinical remis- arthralgia (range \ 1–20%), Clostridium difﬁcile infection sion at 14 weeks and 42% of patients with UC and 31% of (range \ 1–20%), and fatigue (range 1–19%). Infusion- patients with CD at 12 months. As patients comprising the related reactions were uncommon, as were ﬂu/ﬂu-like 12-month cohort likely represent the earliest vedolizumab infections, pruritus, and paresthesia (B 7% for all). users, they could represent a more severe, treatment-re- fractory cohort (most are likely to have failed anti-TNFa Subgroup analysis treatment). According to RCT experiences, greater effec- tiveness should be achieved in biologic-naive patients. In a Clinical remission rates by geographic location real-world setting, this trend could induce higher efﬁcacy rates with continued and earlier use of the drug. Also, in A subgroup analysis by geographic location showed vari- our study, up to approximately one-third of patients with able combined remission rates among patients with UC at CD achieved clinical remission after week 14, suggesting week 14 [range 24% (Germany) to 39% (France and UK)] potential beneﬁts of therapeutic monitoring beyond this and month 12 [range 25% (Germany) to 64% (Sweden)] time point. Despite including patients with more complex (Fig. 6a). Among studies conducted in the USA, remission disease versus RCTs, real-world clinical and CS-free rates were 38% (95% CI 25–52%) at week 14 and 51% at clinical remission rates in UC and CD reported here are month 12. Remission rates among patients with CD also consistent with, and in some cases exceed, vedolizumab varied by geographic location (week 14: range, 19% efﬁcacy reported in the GEMINI trials [5–7]. Moreover, the [Spain] to 37% [UK]; month 12: range, 6% [Netherlands] ﬁndings suggest a similar treatment effect in UC and CD, to 60% [Sweden]) (Fig. 6b). Among studies conducted in despite including patients with more complex disease the USA, remission rates were 27% (95% CI 20–35%) at versus RCTs. week 14 and 35% at month 12. Subgroup analyses in UC and CD biologic-naive patients receiving vedolizumab demonstrated substantially 123 J Gastroenterol (2018) 53:1048–1064 1055 Study Patients Patients Week 6 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 26 121 21 (15–30) Baumgart et al. 10 115 9 (4–15) Random-effects model 14 (6–32) Heterogeneity: P < .01 0 20406080 100 Study Patients Patients Week 14 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 43 121 36 (27–45) Baumgart et al. 22 115 19 (12–28) Kopylov et al. 18 74 24 (15–36) Samaan et al. 68 1 33 (13–59) Shelton et al. 12 52 23 (13–37) Random-effects model 26 (20–34) Heterogeneity: P = .06 0 20406080 100 Study Patients Patients Month 6 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 49 121 41 (32–50) Peerani et al. 40 180 22 (16–29) Samaan et al. 5 10 50 (19–81) Stallmach et al. 90 6 15 (7–27) Zezos et al. 25 57 44 (31–58) Random-effects model 32 (21–44) Heterogeneity: P < .01 0 20406080 100 Study Patients Patients Month 12 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 49 121 40 (32–50) Dulai et al. 74 180 41 (34–49) Eriksson et al. 23 39 59 (42–74) Samaan et al. 7 12 58 (28–85) Stallmach et al. 13 60 22 (12–34) Random-effects model 42 (31–53) Heterogeneity: P < .01 0 20406080 100 123 1056 J Gastroenterol (2018) 53:1048–1064 b Fig. 3 Meta-analysis of CS-free clinical remission rates among studies on the long-term effects of vedolizumab treatment patients with ulcerative colitis receiving vedolizumab at the time on hospitalization rates are warranted. points: a week 6; b week 14; c 6 months; and d 12 months. The size Mucosal healing is an important IBD therapy goal of each square represents the weight assigned to each study based on associated with sustained clinical remission, CS-free clin- sample size. Error bars represent 95% CIs. Diamonds represent the point estimate of the averaged study rates; the lateral tips of the ical remission, and reduced hospitalization and surgery diamonds represent 95% CIs. CI conﬁdence interval, CS corticos- rates [118, 119]. Recent ‘‘treat-to-target’’ draft clinical teroid. Data from Amiot et al. , Baumgart et al. , Kopylov guidelines state that only patients with mucosal healing et al. , Samaan et al. , Shelton et al. , Peerani et al. , (absence of macroscopic signs of active inﬂammation) and Samaan et al. , Stallmach et al. , Zezos et al. , Dulai et al. , Eriksson et al. . Unpublished clinical data provided no/very mild signs or symptoms should be considered as courtesy of Dr. Mark A. Samaan and Dr. Peter Irving from their remitted . Among larger studies (sample size C 100) UK study, 2016 in our systematic review, more than half of patients with UC or CD achieved mucosal healing at 12 months; results for UC were better than reported in GEMINI 1 . improved remission rates versus the overall patient popu- Although data were limited to 12 studies, the observed lation. These results further strengthen evidence that rates of mucosal healing over 12 months were greater than vedolizumab demonstrates greater effectiveness in anti- the combined rates of clinical remission, supporting pre- TNFa-naive patients. Post hoc analyses of GEMINI data vious reports of a lack of clear correlation between clinical indicated greater 12-month remission rates in anti-TNFa- symptom measures and bowel damage assessed by naive patients versus anti-TNFa therapy failures (GEMINI endoscopy/colonoscopy or diagnostic imaging modalities 2 [CD] 49 versus 28%)  or versus anti-TNFa-expe- [121, 122]. Interim results from the LOVE-CD trial rienced patients (GEMINI 1 [UC] 47 versus 36%) . demonstrated that, of 74 patients who underwent endo- Several real-world studies have demonstrated better out- scopy, endoscopic remission (deﬁned as Simple Endo- comes with vedolizumab in anti-TNFa-naive versus anti- scopic Score for CD B 3) was observed in 30% of patients TNFa-experienced patients [24, 36, 38, 46, 114–116]. The at week 26 . Patients with endoscopic response were results from the current study are consistent with these shown to have higher median vedolizumab concentrations ﬁndings. compared with endoscopic nonresponders . Results In the current study in both UC and CD, Swedish from the phase 3b, open-label, VERSIFY study cohorts had higher clinical remission rates, whereas cohorts (NCT02425111) will provide additional insights into rates in Germany and Spain had lower remission rates. The of mucosal healing in CD patients receiving vedolizumab differences in remission rates based on geography need to (manuscript in progress) . be interpreted with caution, however, because of the small Dose escalation is used to address secondary loss of number of studies in this analysis. Several characteristics of response to biologics in the clinical management of IBD IBD patients, including epidemiology, phenotype, and . The studies included here (n =8) genotype, are known to vary with geography . Geo- [23, 33, 37, 41, 46, 57, 75, 108] reported that 4–60% of graphic differences in study population baseline charac- patients required dose escalation up to week 54, with lower teristics [e.g., disease severity at vedolizumab initiation, rates reported in biologic-naive patients (n = 2; range disease duration, prior anti-TNFa use (and number of prior 0–20%). However, the highest rates of dose escalation therapies)], national treatment guidelines, and IBD man- (47–60%) were observed in more complex, treatment-re- agement patterns may also account for variations in fractory UC and CD patients who were included as part of remission rates across geographic locations in our study. a compassionate-use program  and thus are unlikely to This is an area worthy of further investigation, but is be representative of the general IBD population receiving beyond the current analysis. biologics. In 2 studies, dose-escalation rates were lower Five publications included in the current review reported with vedolizumab than with anti-TNFa agents [57, 75]. Of on hospitalization rates both pre-vedolizumab the few studies reporting dose-escalation outcomes (6–12 months before initiation) and post-vedolizumab (N = 4), at least one-third of patients were able to recapture (6 months after initiation); 4 studies [63, 100, 101, 110] response [33, 37, 46, 108]. reported a reduction in post-treatment hospitalization rates, A meta-analysis of 9 studies comprising 1565 adult whereas 1 study  reported no change in hospitalization patients with UC or CD was recently published by Engel rates. Furthermore, a recent study in biologic-naive patients and colleagues . Investigation of rates of clinical (published after the prespeciﬁed date range for this review) remission, clinical response, CS-free clinical remission, reported lower rates of IBD-related surgery and hospital- and safety demonstrated that vedolizumab is efﬁcacious in izations at 6 and 12 months after the ﬁrst infusion of UC and CD and has a favorable safety proﬁle. Our study vedolizumab compared with inﬂiximab . Additional results corroborate their ﬁndings. The overall AE rate 123 J Gastroenterol (2018) 53:1048–1064 1057 Study Patients Patients Week 6 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 33 173 19 (14–26) Baumgart et al. 11 97 11 (6–19) Dulai et al. 10 117 9 (4–15) Random-effects model 13 (8–21) Heterogeneity: P = .03 0 20406080 100 Study Patients Patients Week 14 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 53 173 31 (24–38) Baumgart et al. 19 97 20 (12–29) Kopylov et al. 38 130 29 (22–38) Samaan et al. 5 19 26 (9–51) Shelton et al. 16 85 19 (11–29) Random-effects model 25 (20–31) Heterogeneity: P = .14 0 20406080 100 Study Patients Patients Month 6 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 48 173 28 (21–35) Dulai et al. 21 117 18 (11–26) Samaan et al. 4 10 40 (12–74) Stallmach et al. 9 67 13 (6–24) Random-effects model 22 (15–32) Heterogeneity: P = .03 0 20406080 100 Study Patients Patients Month 12 CS-free Rate (%) 95% CI in remission assessed remission rate (%) Amiot et al. 47 173 27 (21–34) Dulai et al. 40 117 34 (26–44) Eriksson et al. 37 68 54 (42–67) Samaan et al. 3 10 30 (7–65) Stallmach et al. 10 67 15 (7–26) Random-effects model 31 (20–45) Heterogeneity: P = .05 0 20406080 100 123 1058 J Gastroenterol (2018) 53:1048–1064 b Fig. 4 Meta-analysis of CS-free clinical remission rates among reported by Engel and colleagues was 30.6% (6 studies, patients with Crohn’s disease receiving vedolizumab at the time n = 306) compared with a rate of 0–67% (23 studies, points: a week 6; b week 14; c 6 months; and d 12 months. The size n = 2358) in the current study. Nasopharyngitis and of each square represents the weight given to each study based on arthralgia were among the most common AEs reported in sample size. Error bars represent 95% CIs. Diamonds represent the point estimate of the averaged study rates; the lateral tips of the both meta-analyses. diamonds represent 95% CIs. CI conﬁdence interval, CS corticos- A notable point of differentiation between the current teroid. Data from Amiot et al. , Baumgart et al. , Dulai et al. study and the report by Engel and colleagues is the com- , Kopylov et al. , Samaan et al. , Shelton et al. , Dulai prehensiveness of the current study with inclusion of not et al. , Samaan et al. , Stallmach et al. , Eriksson et al. . Unpublished clinical data provided courtesy of Dr. Mark A. Samaan only full-text articles but also congress abstracts, thus and Dr. Peter Irving from their UK study, 2016 allowing for additional effectiveness data to be assessed at relevant treatment time points. The thorough and inclusive approach adopted for the current review facilitated a 100 Study Christensen Chaudrey Schmidt Schmidt Gils Gils Schmidt Pauwels Vivio Peerani Kochhar Dulai Amiot Schmidt Peerani Kochhar Dulai Pauwels Schmidt et al. et al. et al. et al. et al. (a) et al. (b) et al. et al. et al. et al. et al. et al. (a) et al. et al. et al. et al. et al. (a) et al. et al. Time point ≥3 infusions Induction Week 2 Week 6 Week 10 Week 10 Week 14 Week 16 Week 22 Month 6 Month 6 Month 6 Month 6 Month 6 Month 12 Month 12 Month 12 Month 12 Month 12 Ulcerative colitis patients 8 2 15 22 13 19 26 8 20 35 31 63 34 22 76 77 138 3 20 with mucosal healing Ulcerative colitis patients 14 3 60 60 20 29 60 19 29 114 131 180 62 60 114 131 180 6 60 assessed Rate (%) 57 66 25 37 65 66 43 42 69 31 24 35 55 37 67 59 77 50 33 95% CI 33–79 21–94 16–37 26–49 41–85 47–80 32–56 23–64 51–83 23–40 17–32 28–42 43–67 26–49 56–75 50–67 71–83 19–81 23–46 Study Christensen Chaudrey Pauwels Vivio Gils Dulai Kochhar Amiot Dulai Kochhar Pauwels et al. et al. et al. et al. et al. (b) et al. (b) et al. et al. et al. (b) et al. et al. Time point ≥3 infusions Induction Week 16 Week 22 Week 22 Month 6 Month 6 Month 6 Month 12 Month 12 Month 12 Crohn's disease patients 4 6 7 8 5 28 38 17 89 115 1 with mucosal healing Crohn's disease patients 23 30 38 27 28 141 199 57 141 199 17 assessed Rate (%) 17 20 18 30 18 20 19 30 63 58 6 95% CI 7–37 10–37 9–33 16–48 8–36 14–27 14–25 20–43 55–71 51–64 1–27 Fig. 5 Mucosal healing rates among patients with ulcerative colitis , Kochhar et al. , Dulai et al. (a) , Amiot et al. , Dulai a b (a) or Crohn’s disease (b) receiving vedolizumab. Square size et al. (b) . Median time point. Only patients with C 1 follow-up represents the weight given to each study, based on sample size. Error assessment at the speciﬁed time point were included in the analyses. bars represent 95% CIs. CI conﬁdence interval. Christensen et al. Data from the VICTORY Consortium, which contributed the majority , Chaudrey et al. , Schmidt et al. , Gils et al. (a) , of mucosal healing data, used a cumulative incidence analysis, and Gils et al. (b) , Pauwels et al. , Vivio et al. , Peerani et al. remaining studies employed a ‘‘complete’’ case approach Mucosal healing rate (%) Mucosal healing rate (%) J Gastroenterol (2018) 53:1048–1064 1059 Netherlands 50% 48% UK Sweden (n=6) (n=48)** 64% 39% (n=39) (n=18) 24% 39% (n=115) (n=121) Germany 38% (n=93)* 25% France (n=60) US 42% 31% (n=121) (n=42) 51% (n=180) 27% Spain (n=74) Israel 14 weeks 12 months * 3 studies ** 2 studies Sweden UK Netherlands 22% 6% 60% (n=58)** 37% (n=17) (n=68) (n=19) 24% Germany 36% (n=97) (n=173) 27% 21% (n=205)* (n=67) France US 30% 19% 34% 35% (n=173) (n=53) (n=79) (n=212) Spain 35% Belgium (n=130) Israel 14 weeks 12 months * 5 studies ** 2 studies Fig. 6 Subgroup analysis by geographical location showing clinical otherwise, one study was reported at each geographical location. remission rates among patients with a ulcerative colitis and b Crohn’s Random-effects meta-analysis of single proportions was used to disease. The size of each data bubble is proportional to the calculate an overall proportion in cases of [ 1 study corresponding country clinical remission rates. Unless speciﬁed additional subgroup analyses by geographic location and in vedolizumab initiation, dose-escalation rates, and subse- patients with no prior therapy with biologics. The current quent outcomes. analysis also reports outcomes not assessed by Engel and Vedolizumab is a gut-selective integrin antagonist with colleagues, including hospitalization, surgical rates post- no identiﬁed systemic immunosuppressive activity 123 1060 J Gastroenterol (2018) 53:1048–1064 Acknowledgements The systematic literature review (including [5–7, 127–130]. Real-world safety data reported here are assessment of the level of evidence) was performed by PHMR Lim- consistent with those from the GEMINI trials, with no new ited. Unpublished clinical data were provided courtesy of Dr. Mark A. or unexpected safety signals . This tolerability proﬁle Samaan and Dr. Peter Irving from their UK study, 2016. The authors may help to improve treatment persistence [115, 116], also wish to acknowledge Ray Liu and Yanyan Zhu for their helpful discussions. We thank Vinay Pasupuleti, PhD, and Rezan Sahinkaya, thereby potentially positively affecting long-term out- PhD, ProEd Communications, Inc., for medical editorial assistance comes. Postoperative complication rates in the current with this manuscript. All authors have approved the ﬁnal version of analysis ranged from 13 to 65% [89, 102, 131–133]. A the article, including the authorship list. recent meta-analysis assessing the impact of preoperative vedolizumab treatment on the rate of postoperative com- Author contributions DD and JMK: study concept and design; DD: conduct of literature review (with PHMR Limited—acknowledged); plications in real-world patients with IBD demonstrated no GH: analysis of data; SS, AD, LPB, MM, RC, and EVL: interpreta- increased risk of postoperative infectious or total overall tion of data and adding clinical context; DD and JMK: drafting of the postoperative complications compared with either preop- manuscript. All authors critically reviewed and revised the manuscript erative anti-TNFa therapy or no biologic therapy . for important intellectual content and approved the ﬁnal version of the manuscript before submission. In addition to the limitations of real-world studies, the limitations of this meta-analysis include potential publi- Funding Takeda sponsored medical writing assistance, which was cation bias. Egger’s weighted regression statistic was cal- provided by Khalid Siddiqui of Chameleon Communications Inter- culated for only 1 analysis (CD at week 14) and in this case national Ltd, UK (a Healthcare Consultancy Group Company), Rezan Sahinkaya, PhD, and Vinay Pasupuleti, PhD, of ProEd Communica- the P value suggested that bias was unlikely. The tions, Inc. Authors from Takeda were involved in the statistical remaining analyses did not include enough studies (C 10) analysis and interpretation of data, which led to co-authorships to allow an assessment of publication bias . However, according to the level of contribution. the inclusion of studies published as abstracts as in the current analysis may help minimize the risk of publication Compliance with ethical standards bias. A moderate to high degree of between-study statis- Conﬂict of interest Stefan Schreiber has received honoraria from tical heterogeneity was detected in some analyses. Major AbbVie, Celltrion, MSD, Pﬁzer, and Takeda. Axel Dignass has no contributory factors to this heterogeneity may include the conﬂict of interest. Laurent Peyrin-Biroulet has received lecture fees different disease activity measures and variable thresholds from MSD, Abbvie, Janssen, Takeda, Celltrion, Pﬁzer, BMS, Phar- macosmos, Shire, Genentech, Mitsubishi, Ferring, Norgine, Tillots, used to assess clinical response and remission, which may Vifor, UCB Pharma, Hospira, Boehringer-Ingelheim, and Lilly. Greg impact the extrapolation of these ﬁndings to clinical Hather owns stock in Takeda Pharmaceuticals and is an employee of practice. Nevertheless, the current meta-analysis attempted Takeda Global Research and Development. Dirk Demuth is an to address bias by combining study data using a weighted employee of Takeda International, UK Branch. Mahmoud Mosli has no conﬂict of interest. Rebecca Curtis is a former employee of Takeda average based on sample size. Moreover, the consistency International, UK Branch. Javaria Mona Khalid owns stock in Takeda of evidence levels (i.e., most studies were level 4) did not Pharmaceuticals International and is an employee of Takeda Inter- allow for sensitivity analysis to be conducted by study national, UK Branch. Edward V. Loftus, Jr, has received research quality. Finally, real-world data may be less stringent than support from and has served as a consultant for Takeda. RCT data, which are obtained by rigorous data collection Open Access This article is distributed under the terms of the and quality control of data integrity. However, real-world Creative Commons Attribution 4.0 International License (http://crea data provide greater insight into the effectiveness of tivecommons.org/licenses/by/4.0/), which permits unrestricted use, vedolizumab in heterogenous and more complex patient distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a populations that are more representative of clinical link to the Creative Commons license, and indicate if changes were practice. made. References Conclusions 1. Gomollo ´ n F, Dignass A, Annese V, et al. 3rd European evi- The results from this meta-analysis of real-world data dence-based consensus on the diagnosis and management of conﬁrm the effectiveness of vedolizumab in inducing long- Crohn’s disease 2016: part 1: diagnosis and medical manage- term clinical response, clinical remission, CS-free clinical ment. J Crohns Colitis. 2017;11(1):3–25. 2. Harbord M, Eliakim R, Bettenworth D, et al. 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