ACG Clinical Guideline: Management of Crohn's Disease in Adults.

Crohn's disease is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of Crohn's disease has steadily increased over the past several decades. The diagnosis and treatment of patients with Crohn's disease has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the American College of Gastroenterology and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with Crohn's disease. These guidelines are established for clinical practice with the intent of suggesting preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When exercising clinical judgment, health-care providers should incorporate this guideline along with patient's needs, desires, and their values in order to fully and appropriately care for patients with Crohn's disease. This guideline is intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. To evaluate the level of evidence and strength of recommendations, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time.

Correction: ACG Clinical Guideline: Management of Crohn's Disease in Adults.

Since the publication of these Guidelines, the authors have noticed an error in the text on page 15. The incorrect statement is.

A novel device for improving visualization in an inadequately prepared colon.

BACKGROUND AND AIMS: Adequate bowel preparation is crucial for a quality colonoscopy. Poor bowel preparation can result in longer procedural times, missed adenomas, earlier repeat procedures, increase costs, and decreased patient satisfaction. Pure-Vu (MOTUS GI, Tirat Carmel, Israel) is a system that facilitates intraprocedural cleaning of a poorly prepared colon during a colonoscopy by irrigating the colon and evacuating the fluid and feces. The study aims were to evaluate Pure-Vu's cleansing capabilities and its usability and safety in a live animal colon. METHODS: The Pure-Vu system was used by 4 experienced gastroenterologists in 35 Yorkshire cross swine (66% female) that received a reduced bowel preparation to ensure an inadequate bowel preparation at baseline. Before colonoscopy the Pure-Vu was attached to the colonoscope, and the baseline prep was assessed during insertion. The Pure-Vu system was then used to cleanse the colon and the prep then assessed after Pure-Vu use. RESULTS: No adverse effects and no failed or prematurely terminated cases were noted. Fourteen percent of the swine colons were adequately prepped at baseline (median Boston Bowel Preparation Scale [BBPS] score = 0 [25th percentile = 0; 75th percentile = 1; interquartile range = 1]) and improved to 100% after use of Pure-Vu (Wilcoxon signed rank test P < .001) (median BBPS score = 3 [25th percentile = 3; 75th percentile = 3; interquartile range = 0]). The physicians found Pure-Vu easy and intuitive to operate. CONCLUSIONS: The Pure-Vu system effectively cleaned inadequately prepped swine colons and proved to be easy to use. The Pure-Vu device, applied in clinical practice, may result in improved overall prep quality and a reduction in repeat examinations because of inadequately prepped colons.

Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.

BACKGROUND AND AIMS: Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells. METHODS: We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS. RESULTS: One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure. CONCLUSION: Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.).

Retention associated with video capsule endoscopy: systematic review and meta-analysis.

BACKGROUND AND AIMS: Video capsule endoscopy (VCE) has become a major diagnostic tool for small-bowel evaluation. However, retention of the video capsule endoscope remains a major concern. METHODS: We performed a systematic review of VCE retention rates by using Pubmed and SCOPUS (1995-2015). We included studies that enrolled at least 10 patients, included VCE retention rates, and separated retention rates by indication. We used Comprehensive Meta-Analysis (Version 3.0) to calculate pooled prevalence rates with 95% confidence intervals (CIs) and assessed heterogeneity by using the Cochran Q statistic. RESULTS: We included 25 studies (N = 5876) for patients undergoing VCE for evaluation of potential small-bowel bleeding, 9 studies (N = 968) for patients with suspected inflammatory bowel disease (IBD), 11 studies (N = 558) for patients with established IBD, and 8 studies for patients (N = 111) undergoing VCE for evaluation of abdominal pain and/or diarrhea. We used a random effects model and found that the pooled retention rate was 2.1% for patients with suspected small-bowel bleeding (95% CI, 1.5%-2.8%). Retention rates were 3.6% (95% CI, 1.7%-8.6%) for suspected IBD, 8.2% (95% CI, 6.0%-11.0%) for established IBD, and 2.2% (95% CI, 0.9%-5.0%) for abdominal pain and/or diarrhea. Based on subgroup analysis, subsequent VCE completion rates after performance of a patency capsule or CT enterography in patients with IBD to exclude retentions due to strictures was 2.7% (95% CI, 1.1%-6.4%). Reasons for retention were provided in 60 (77%) studies. The most common reasons for retention were small-bowel strictures, although etiology was not provided in all studies. CONCLUSION: VCE retention occurs in approximately 2% of patients undergoing evaluation for small-bowel bleeding and is most likely due to small-bowel strictures. Retention rates in patients with suspected or known IBD were approximately 4% and 8%, based on our meta-analysis. These rates decreased by half in those studies that used either a patency capsule or CT enterography to assess patency before performing VCE.

Association between breast cancer and the risk of colorectal cancer.

BACKGROUND: The literature to date has suggested a potential increase in colorectal cancer (CRC) among patients with breast cancer. METHODS: We performed a systematic review of the literature and included 37 retrospective cohort studies and 8 case-control studies. The primary aim was to determine the prevalence of CRC. Secondary aims included analysis of adenomatous polyps and analysis of CRC prevalence by age. We calculated pooled prevalence rates and odds ratios (ORs) using random effects models with 95% confidence intervals (CI). RESULTS: We identified 1,055,917 individuals with breast cancer among whom 9097 cases of CRC were detected. The pooled event rate for CRC was 0.7% (95% CI, 0.6%-0.9%; I2=97%). Four case-control studies reported prevalence of CRC (N=17,873 patients with breast cancer and 70,366 controls), including 46 cases of CRC in the patients with breast cancer, and 272 CRC in the controls (OR, 1.2; 95% CI, 0.4%-3.7%; P = .7). Six studies reported prevalence of advanced adenomas in patients with breast cancer (N=1087) compared with controls (N=1356) with 62 cases of advanced adenomas in patients compared with 47 in the controls (OR, 1.5; 95% CI, 0.97-2.2; P = .07). In patients with breast cancer <50 years old (4 studies, N=64,706), the pooled OR was increased (OR, 2.5; 95% CI, 1.7-3.5; P =.001). In 3 studies of women <45 years old (N=92,594), the risk was increased (OR, 2.3; 95% CI, 1.7-2.6; P < .001). CONCLUSIONS: Patients with breast cancer should not undergo CRC screening at intervals different from the general population. In patients with breast cancer <50 years old, CRC screening should be considered at age 45 years.

ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus.

Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE.

In-hospital weekend outcomes in patients diagnosed with bleeding gastroduodenal angiodysplasia: a population-based study, 2000 to 2011.

BACKGROUND AND AIMS: GI angiodysplastic (GIAD) lesions are an important cause of blood loss throughout the GI tract, particularly in elderly persons. The aim of this study was to determine whether mortality rates in patients with GIAD were higher for weekend compared with weekday hospital admissions. METHODS: We performed a retrospective study using the National Inpatient Sample database from 2000 to 2011 including inpatients with an International Classification of Diseases, Ninth Revision, Clinical Modification code for gastrointestinal GIAD (code 537.82 or 537.83). We assessed rates of delayed endoscopy (examinations performed >24 hours after admission), intensive care unit (ICU) admissions, and in-hospital mortality rates. Bivariate and multivariate logistic regression analyses were performed to identify risk factors for mortality. RESULTS: There were 85,971 discharges for GIAD between 2000 and 2011, of which 69,984 (81%) were weekday hospital admissions and 15,987 (19%) were weekend admissions. Patients with weekend versus weekday admissions were more likely to undergo delayed endoscopic examination (35% vs 26%, P ≤ .0001). Mortality rates were higher for patients with weekend admissions (2% vs 1%, P = .0002). The adjusted odds ratio (aOR) for inpatient mortality associated with weekend admissions was elevated (2.4; 95% confidence interval [CI], 1.5-3.9; P = .0005). Rates of delayed endoscopic examinations were lower in patients with higher socioeconomic status (aOR = 0.77; 95% CI, 0.68-0.88). ICU admission rates were higher for weekend compared with weekday admissions (8% vs 6%, P = .004). The presence of a delayed endoscopic examination was associated with an increased length of stay of 1.3 days (95% CI, 1.2-1.4 days). CONCLUSIONS: Weekend admissions for angiodysplasia were associated with higher odds of mortality, ICU admissions, higher rates of delayed endoscopic procedures, longer lengths of stay, and higher hospital charges.

ACG Clinical Guideline: Diagnosis and Management of Small Bowel Bleeding.

Bleeding from the small intestine remains a relatively uncommon event, accounting for ~5-10% of all patients presenting with gastrointestinal (GI) bleeding. Given advances in small bowel imaging with video capsule endoscopy (VCE), deep enteroscopy, and radiographic imaging, the cause of bleeding in the small bowel can now be identified in most patients. The term small bowel bleeding is therefore proposed as a replacement for the previous classification of obscure GI bleeding (OGIB). We recommend that the term OGIB should be reserved for patients in whom a source of bleeding cannot be identified anywhere in the GI tract. A source of small bowel bleeding should be considered in patients with GI bleeding after performance of a normal upper and lower endoscopic examination. Second-look examinations using upper endoscopy, push enteroscopy, and/or colonoscopy can be performed if indicated before small bowel evaluation. VCE should be considered a first-line procedure for small bowel investigation. Any method of deep enteroscopy can be used when endoscopic evaluation and therapy are required. VCE should be performed before deep enteroscopy if there is no contraindication. Computed tomographic enterography should be performed in patients with suspected obstruction before VCE or after negative VCE examinations. When there is acute overt hemorrhage in the unstable patient, angiography should be performed emergently. In patients with occult hemorrhage or stable patients with active overt bleeding, multiphasic computed tomography should be performed after VCE or CTE to identify the source of bleeding and to guide further management. If a source of bleeding is identified in the small bowel that is associated with significant ongoing anemia and/or active bleeding, the patient should be managed with endoscopic therapy. Conservative management is recommended for patients without a source found after small bowel investigation, whereas repeat diagnostic investigations are recommended for patients with initial negative small bowel evaluations and ongoing overt or occult bleeding.

Significantly higher rates of gastrointestinal bleeding and thromboembolic events with left ventricular assist devices.

BACKGROUND & AIMS: The risk of gastrointestinal (GI) bleeding (GIB) and thromboembolic events may increase with continuous-flow left ventricular assist devices (CF-LVADs). We aimed to characterize GIB and thromboembolic events that occurred in patients with CF-LVADs and compare them with patients receiving anticoagulation therapy. METHODS: We performed a retrospective analysis of 159 patients who underwent CF-LVAD placement at 2 large academic medical centers (mean age, 55 ± 13 y). We identified and characterized episodes of GIB and thromboembolic events through chart review; data were collected from a time period of 292 ± 281 days. We compared the rates of GIB and thromboembolic events between patients who underwent CF-LVAD placement and a control group of 159 patients (mean age, 64 ± 15 y) who received a cardiac valve replacement and were discharged with anticoagulation therapy. RESULTS: Bleeding events occurred in 29 patients on CF-LVAD support (18%; 45 events total). Sixteen rebleeding events were identified among 10 patients (range, 1-3 rebleeding episodes/patient). There were 34 thrombotic events among 27 patients (17%). The most common source of bleeding was GI angiodysplastic lesions (n = 20; 44%). GIB and thromboembolic events were more common in patients on CF-LVAD support than controls; these included initial GIB (18% vs 4%, P < .001), rebleeding (6% vs none, P = .001), and thromboembolic events (17% vs 8%, P = .01). CONCLUSIONS: Patients with CF-LVADS receiving anticoagulants have a significantly higher risk of GIB and thromboembolic events than patients receiving anticoagulants after cardiac valve replacement surgery. GI angiodysplastic lesions are the most common source of bleeding.

Management of gastrointestinal angiodysplastic lesions (GIADs): a systematic review and meta-analysis.

OBJECTIVES: Gastrointestinal angiodysplastic lesions (GIADs) are defined as pathologically dilated communications between veins and capillaries. The objective of this systematic review and meta-analysis was to determine the efficacy of available treatment modalities for GIADs. METHODS: We identified eligible studies by searching through PubMed, SCOPUS, and Cochrane central register of controlled trials. We searched for clinical trials examining the efficacy of endoscopic, pharmacologic, or surgical therapy for GIADs. Data were pooled using a random-effects model, and the effect of response to medical or surgical therapy was reported as odds ratios with 95% confidence intervals (CIs). Data and quality indicators were extracted by two authors from 22 studies, including 831 individuals with GIADs. The analysis included 623 patients treated with endoscopic therapy, 63 with hormonal therapy, 72 patients with octreotide, and 73 status post aortic valve replacement surgery. RESULTS: Hormonal therapy, based on two case-control studies, was not effective for bleeding cessation (odds ratio: 1.0, 95% CI: 0.5-1.96). On the basis of 14 studies including patients with gastric, colonic, and small-bowel GIADs, endoscopic therapy was effective as initial therapy, but the pooled recurrence bleeding rate was 36% (95% CI: 28-44%) over a mean (±s.d.) of 22±13 months. The event rate for re-bleeding increased to 45% (95% CI: 37-52%) when studies including only small-bowel GIADs were included (N=341). In four studies assessing the efficacy of somatostatin analogs, the pooled odds ratio was 14.5 (95% CI: 5.9-36) for bleeding cessation. In two studies assessing the role of aortic valve replacement (AVR) in 73 patients with Heyde's syndrome, the event rate for re-bleeding was 0.19 (95% CI: 0.11-0.30) over a mean follow-up period of 4 years postoperatively. CONCLUSIONS: Over one-third of patients with GIADs experienced re-bleeding after endoscopic therapy. Somatostatin analogs and AVR for Heyde's syndrome appeared to be effective therapy for GIADs.

GI bleeding in patients with continuous-flow left ventricular assist devices: a systematic review and meta-analysis.

BACKGROUND: Patients with left ventricular assist devices (LVADs) are at increased risk of GI bleeding (GIB), primarily from GI angiodysplastic lesions (GIAD). OBJECTIVE: To perform meta-analysis of the medical literature in order to determine prevalence and risk factors for GIB. DESIGN: A literature search was performed to identify studies reporting GIB in LVAD patients. We extracted rates of prevalence, rebleeding, and overall mortality from each study. Pooled event rates and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. SETTING: Meta-analysis of 17 case-control and cohort studies. PATIENTS: A total of 1839 LVAD patients of whom 1697 (92%) had continuous-flow LVADs. RESULTS: The pooled prevalence of GIB in LVAD patients was 23% (95% CI, 20.5%-27%). Subgroup analysis demonstrated that older age (standard difference in means (SDm), 0.69; 95% CI, 0.23-1.15), and elevated creatinine (SDm, 0.65; 95% CI, 0.12-1.18, P = .02) were associated with GIB. Risk factors not associated with GIB included LVAD as destination therapy (OR 1.85; 95% CI, 0.8-4.3), prior history of GIB (OR 2.22; 95% CI, 0.83-5.96), hypertension (OR 1.6; 95% CI, 0.87-2.97), and/or the presence of a continuous-flow LVAD (OR 4.5; 95% CI, 2.1-9.5). Recurrence of GIB occurred in 9.3% (95% CI, 7%-12%), with a GIB mortality rate of 23% (95% CI, 16%-32%). The pooled event rates were 48% (95% CI, 39%-57%) for upper GIB, 22% (95% CI, 16%-31%) for lower GIB, and 15% (95% CI, 8%-25%) for small-bowel bleeding. GIAD in the proximal GI tract were the most common cause of GIB (29%). LIMITATIONS: Lack of information regarding endoscopic therapy and follow-up in most studies. CONCLUSIONS: The prevalence of GIB is increased in patients with continuous-flow LVADs, primarily secondary to the presence of GIAD.

Proton pump inhibitors and potential interactions with clopidogrel: an update.

Clopidogrel, an antiplatelet agent, is increasingly prescribed for patients with recent stroke, myocardial infarction, acute coronary syndrome, and/or patients post-coronary stent insertion to prevent recurrent cardiovascular events. Since clopidogrel can increase the risk of gastrointestinal hemorrhage, co-administration of proton pump inhibitors (PPIs) has been recommended, particularly in patients at high risk. In 2009, the FDA issued warnings about potential interactions between clopidogrel and PPIs, given the fact that both drugs are metabolized via the cytochrome P450 pathway. Prior studies have demonstrated significant reduction in platelet inhibition when PPI therapy is administered to subjects on clopidogrel therapy. Two meta-analyses were published in 2010 and 2011, the first suggesting association of PPIs with adverse cardiovascular events when observational studies were examined, but noting that the results were limited by the presence of significant heterogeneity. The second meta-analysis did not find a significant increase in the risk of adverse primary events (which included all cause mortality, cardiovascular death, myocardial infarction, or stroke), and concluded that analysis of the data from two randomized controlled trials yielded a risk difference of zero. An updated literature search was performed to assess clinical studies describing interactions between PPIs and clopidogrel published from 2011-2012. The majority of these studies did not show significant interactions when primary cardiac outcomes were considered. More importantly, the newer data demonstrated that PPI usage independently was a risk factor for adverse CV outcomes, since most PPI users were older patients who were more likely to have concomitant co-morbid conditions. Two updated reviews also concluded that the presence of confounding factors likely explained differences in results between studies, and that there were no significant differences in effects on clopidogrel between individual proton pump inhibitors. Overall, clinicians can assure their patients that combination therapy is safe when indicated in a patient at high risk of GI bleeding, but they should also stop PPI therapy if it is not clinically indicated.

Distal esophageal spasm: an update.

Distal esophageal spasm (DES) is an esophageal motility disorder that presents clinically with chest pain and/or dysphagia and is defined manometrically as simultaneous contractions in the distal (smooth muscle) esophagus in ≥20% of wet swallows (and amplitude contraction of ≥30 mmHg) alternating with normal peristalsis. With the introduction of high resolution esophageal pressure topography (EPT) in 2000, the definition of DES was modified. The Chicago classification proposed that the defining criteria for DES using EPT should be the presence of at least two premature contractions (distal latency<4.5 s) in a context of normal EGJ relaxation. The etiology of DES remains insufficiently understood, but evidence links nitric oxide (NO) deficiency as a culprit resulting in a disordered neural inhibition. GERD frequently coexists in DES, and its role in the pathogenesis of symptoms needs further evaluation. There is some evidence from small series that DES can progress to achalasia. Treatment remains challenging due in part to lack of randomized placebo-controlled trials. Current treatment agents include nitrates (both short and long acting), calcium-channel blockers, anticholinergic agents, 5-phosphodiesterase inhibitors, visceral analgesics (tricyclic agents or SSRI), and esophageal dilation. Acid suppression therapy is frequently used, but clinical outcome trials to support this approach are not available. Injection of botulinum toxin in the distal esophagus may be effective, but further data regarding the development of post-injection gastroesophageal reflux need to be assessed. Heller myotomy combined with fundoplication remains an alternative for the rare refractory patient. Preliminary studies suggest that the newly developed endoscopic technique of per oral endoscopic myotomy (POEM) may also be an alternative treatment modality.

Is there a role for angiography in patients with obscure overt bleeding?

Obscure gastrointestinal hemorrhage remains a challenging but uncommon clinical scenario. Video capsule endoscopy (VCE) has been recommended as the third diagnostic test after normal upper and lower endoscopic examinations. A recent randomized controlled trial comparing immediate VCE to angiography demonstrated a superior diagnostic yield for VCE compared with angiography. However, long-term outcomes, including rebleeding, hospitalization rates, and death, did not differ between the two cohorts. Although VCE appears to be superior to other testing modalities for overall diagnostic yield, the clinical outcomes ultimately depend upon the type of lesion detected. Vascular lesions, mainly small bowel angiodysplasia, can be expected to have the highest rates of rebleeding, despite endoscopic therapy, and have been associated with the presence of comorbid conditions.

Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature.

BACKGROUND: Published data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting. AIM: To perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses. METHODS: Primary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re-hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model. RESULTS: We reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI -0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01-0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03-0.06). CONCLUSIONS: In patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders.