Proton Pump Inhibitor Preventing Upper Gastrointestinal Injury In Patients On Dual Antiplatelet Therapy After CABG (DACAB-GI-2)

Evaluation of the Efficacy of Different Duration of a Proton Pump Inhibitor in the Prevention of Upper Gastrointestinal Mucosal Injury in Patients Taking 12-month Dual Antiplatelet Therapy After Coronary Artery Bypass Grafting

The purpose of this study is to compare the efficacy and safety for 12- vs. 1-month of pantoprazole treatment in preventing dual antiplatelet therapy (DAPT)-related upper gastrointestinal mucosal injury after coronary artery bypass grafting (CABG).

To date, there has been no study using esophagogastroduodenoscopy (EGD) to compare the differences in upper gastrointestinal mucosal injury (including reflux esophagitis) after 6 and 12 months of PPI treatment combined with two different DAPT regimens (clopidogrel plus aspirin or ticagrelor plus aspirin).

Study Overview

• Status: Active, not recruiting
• Conditions: Coronary Artery Bypass; Gastrointestinal Ulcer (Peptic) or Erosion; Anti-Platelet Therapy
• Intervention / Treatment: Drug: Pantoprazole

Detailed Description

This prospective trial was designed as a single-center, open-label, randomized controlled trial with patients allocated in a ratio of 1:1. Within 3 days after CABG, patients willing to participate in the study will be carefully evaluated by a cardiac surgeon together with a gastroenterologist based on inclusion and exclusion criteria. Patients will be followed up to 12 months post-randomization unless death. The outcome will be collected at 2±1 days, 9±2 days, 1 month, 3 months (phone call), 6 months, 9 months (phone call), and 12 months after CABG surgery, respectively. 13C urea breath testing is used to detect Helicobacter pylori (H. pylori) infection before enrollment. At 6 and 12 months post-randomization, routine laboratory tests and EGD will be performed respectively. Computed tomographic angiography (CTA) or coronary angiography (CAG) is also required at 12 months post-randomization.

Definition of end of the study

1. The date on which the last subject completed the last follow-up was the endpoint of this study.
2. During the follow-up period, if the patient's biopsy pathological report showed that EGD detects precancerous lesions (e.g., atypical hyperplasia, low-grade or high-grade internal neoplasia, etc.) or malignant lesions.
3. Patients randomized to the control group (1-month pantoprazole treatment group) should continue PPI treatment if GERD-Q questionnaire score 8, endoscopic findings of reflux esophagitis (LA-A and above), gastroduodenal mucosal injury of modified Lanza score of 4, or upper gastrointestinal bleeding at any time during the follow-up period.

Following the ITT principle, all patients randomized in this study should be evaluated for primary and secondary endpoints regardless of changes in PPI treatment. Thus, patients in the 1-month pantoprazole treatment group required PPI treatment at any time after 1 month and could also be assessed for primary and secondary endpoints.

According to the results of the preliminary study, the cumulative incidence rate of severe gastric and duodenal bulb erosion and ulcers of the 1-month PPI treatment group is assumed to be 36%, and that of the 12-month PPI treatment group was assumed to be 18%. Based on a two-sided α of 0.05 and a randomization ratio of 1:1, a total of 186 subjects are required to provide a power of 80%. Considering a 20% drop-out rate, the sample size of 232 subjects was determined.

In this study, all subjects received pantoprazole treatment for at least 1 month after CABG. Due to the COVID-19 pandemic, some subjects are unable to return to the center for study drugs and/or follow-up 1 month after the randomization. Those subjects who are unable to receive subsequent randomization intervention, will be excluded from the modified full analysis set and not included in the effectiveness analysis. Considering the statistical power of the study, randomized subjects will be added until the effective randomized intervention number reaches the predetermined sample size.

Two subgroup analyses will be performed in this study, including (1) H. pylori infection: negative and positive; (2) DAPT: aspirin + clopidogrel and aspirin + ticagrelor.

• Study Type: Interventional
• Enrollment (Estimated): 232
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lifen Yu, MD, Ph.D; Phone Number: 0086-13641937166; Email: ylf10975@rjh.com.cn
• Study Contact Backup: Name: Yunpeng Zhu, MD; Phone Number: 0086-13816819346; Email: zyp12220@rjh.com.cn

Study Locations

• China
  • Shanghai, China, 200025
    • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this study:

1. Provision of signed informed consent prior to any study specific procedures.
2. Male or female, age ≥ 18 years at the time of consent.
3. Planned or initiated use of 12 months of DAPT (aspirin plus clopidogrel or aspirin plus ticagrelor) immediately following primary isolated elective CABG surgery.

Exclusion Criteria:

Patients should not enter the study if any of the following exclusion criteria are fulfilled.

1. History of previous active peptic ulcer within 3 months prior to enrollment.
2. Planned use of PPIs to treat acid-associated disorders (e.g. gastroesophageal reflux disease, GERD)
3. Contraindications for aspirin, clopidogrel, ticagrelor and pantoprazole use (e.g. known allergy)

4. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices, that cannot be stopped for the course of the study.

   • Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir
   • CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses > 40mg daily or lovastatin at doses > 40mg daily.
5. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin.
6. Women of child-bearing potential who are not willing to use a medically accepted method of contraception that is considered reliable in the judgement of investigator OR women who have a positive pregnancy test at enrollment or randomization OR women who are breasting-feeding.
7. Inability of patient to understand and/or comply with study procedures and/or follow up, in the opinion of the investigator, OR any conditions that, in the opinion of the investigator, many render the patient unable to complete the study.
8. Any condition outside the atherothrombotic study area with a life expectancy of less than 1 year.
9. Participation in another clinical study with an investigational product within 28 days prior to enrolment or previous randomization to an investigational product in another ongoing clinical study.
10. Any condition which in the opinion of the investigator would make it unsafe or unsuitable for the patient to participate in this study (eg, long-term concomitant treatment with non-steroidal anti-inflammatory drugs [NSAIDs])

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: One month of therapy; Pantoprazole, 40mg, tablet, oral, once daily for 1 month	Drug: Pantoprazole; Pantoprazole (40mg qd) will be concomitant used with DAPT; Other Names: PANTOLOC, Tablet from Takeda Pharmaceutical Company Limited
Experimental: Twelve months of therapy; Pantoprazole, 40mg, tablet, oral, once daily for 12 months	Drug: Pantoprazole; Pantoprazole (40mg qd) will be concomitant used with DAPT; Other Names: PANTOLOC, Tablet from Takeda Pharmaceutical Company Limited

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with gastroduodenal erosions and ulcers evaluated by EGD.	Gastroduodenal erosions and ulcers will be assessed according to the Lanza Endoscopic Scoring System. Lanza score is a categorical score (0-4) and defined as follows: 0, normal; 1, mucosal hemorrhages only; 2, 1-2 erosions; 3, 3-10 erosions; 4, >10 erosions or an ulcer ≥3 mm. In addition, ≥1 ulcer with a diameter no less than 5mm will be grouped separately.	within 12 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with gastroduodenal erosions and ulcers evaluated by EGD.	Gastroduodenal erosions and ulcers will be assessed according to the Lanza Endoscopic Scoring System (0-4). In addition, ≥1 ulcer with a diameter ≥5mm will be grouped separately.	6 months after randomization
Cumulative rate of patients with upper gastrointestinal bleeding (UGIB) according to the modified TIMI criteria.	According to the definition of non-CABG related bleeding in the modified TIMI criteria, the severity of UGIB is classified into 3 grades: major, minor and minimal. 1, Major: Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL. 2, Minor: Clinically overt signs of UGIB, resulting in hemoglobin drop of 3 to <5 g/dL. 3, Minimal: Any overt bleeding event that does not meet the criteria above. According to the consensus updated by the Asia-Pacific working group in 2018, patients with hemodynamic shock and signs of UGIB should be offered urgent endoscopy after resuscitation and stabilization (Gut 2018; 67:1757-68).	within 12 months after randomization
Percentage of patients with reflux esophagitis evaluated by EGD.	According to the Los Angeles classification, endoscopic reflux esophagitis was assigned a grade from A to D.	12 months after randomization
Percentage of patients with reflux esophagitis evaluated by EGD.	According to the Los Angeles classification, endoscopic reflux esophagitis was assigned a grade from A to D.	6 months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative rate of patients with major adverse cardiovascular events (MACE).	MACE: composite of cardiovascular death, myocardial infarctions, or stroke.	up to 12 months
The failure rate of grafts assessed by computed tomographic angiography or coronary angiography.	Graft failure was assessed according to the modified Fitzgibbon classification: Stenosis ≥50% or occlusion of the graft or distal anastomosis (type B or O)	up to 12 months
Cumulative rate of patients with all-cause death	All-cause death: Death from all causes during the follow-up.	up to 12 months

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Investigators: Principal Investigator: Lifen Yu, MD, Ph.D, Department of Gastroenterology, Ruijin Hospital; Principal Investigator: Qiang Zhao, MD, Ph.D, Department of Cardiovascular Surgery, Ruijin Hospital; Study Director: Yunpeng Zhu, MD, Department of Cardiovascular Surgery, Ruijin Hospital

Publications and helpful links

General Publications

• Zhu Y, Wang X, Yang Y, Liu L, Zhao Q, Yu L. Proton pump inhibitor in the prevention of upper gastrointestinal mucosal injury associated with dual antiplatelet therapy after coronary artery bypass grafting (DACAB-GI-2): study protocol for a randomized controlled trial. Trials. 2022 Jul 15;23(1):569. doi: 10.1186/s13063-022-06464-w.

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2019
• Primary Completion (Estimated): December 30, 2023
• Study Completion (Estimated): January 30, 2024

Study Registration Dates

• First Submitted: April 5, 2019
• First Submitted That Met QC Criteria: April 8, 2019
• First Posted (Actual): April 9, 2019

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Prevention; Antiplatelet; Gastrointestinal; Coronary artery bypass grafting; Mucosal injury
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Pantoprazole
• Other Study ID Numbers: IISR-2016-101603 (RJ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No