Introduction

Patients with ischemic heart disease have a high risk to develop gastrointestinal bleeding because of antiplatelet therapy. It is argued that these patients might need a higher hemoglobin level for the oxygen demand when bleeding occurs [1-3]. There is little data about blood transfusion strategy for patients with ischemic heart disease complicated with acute upper gastrointestinal bleeding.

Aims & Methods

We designed a multicenter, prospective, randomized controlled trial to compare the outcomes of restrictive blood transfusion strategy with liberal blood transfusion strategy.
From 2019 June, we prospectively recruited 126 ischemic heart disease patients complicated with acute upper gastrointestinal bleeding. All of them were randomly assigned to restrictive blood transfusion group (blood transfusion when hemoglobin ≤ 80g/L) or liberal blood transfusion group (blood transfusion when hemoglobin ≤ 100g/L). The primary endpoint was 30 days rebleeding rate after randomization.

Results

There were 64 patients received restrictive blood transfusion, and 62 had liberal blood transfusion. The baseline characteristics, including sex, age, hemoglobin concentration, Glasgow-Blatchford score, endoscopic findings, types of ischemic heart disease, history of coronary angiography, use of proton pump inhibitor and hemostatic drugs were similar in the two groups. In an intention-to-treat (ITT) analysis, 13 (19.7%) of the restrictive blood transfusion group and 9 (14.3%) of the liberal blood transfusion group reached the primary endpoint (HR: 0.84, 95% CI: 0.56-1.25, p=0.414) (Table 1). In a per-protocol (PP) analysis, 10 of 48 (20.8%) in the restrictive blood transfusion group compared 5 of 22 (22.7%) in the liberal blood transfusion group occurred rebleeding in 30 days after randomization (HR: 1.04, 95% CI: 0.70-1.55, p=0.858). The 30 days all-cause death were similar in the two groups (HR: 0.76, 95% CI: 0.34-1.73, p=0.587 in ITT analysis; HR: 1.38, 95% CI: 0.34-5.58, p=0.566 in PP analysis). The hospital stay length (8.95±4.99 vs. 8.52±4.68, days, in ITT analysis) were reduced in liberal blood transfusion group. There was a reduction in 30-day major cardiovascular events in liberal blood transfusion group (HR: 0.52, 95% CI: 0.43-0.81, p=0.017 in ITT analysis; HR: 0.90, 95% CI: 0.58-1.40, p=0.677 in PP analysis). Of these, 6 (9.4%) patients in restrictive blood transfusion group had heart failure, 4 (6.3%) had myocardial infarction and 2 (3.1%) had both heart failure and myocardial infarction, while 2 (3.2%) patients in liberal blood transfusion group had heart failure and 1 (1.6%) had myocardial infarction.
Table 1. Outcomes of both groups

Treatment outcomes	Restrictive blood transfusion group n= 64	Liberal blood transfusion group n= 62	HR (95%CI)	p
30 days rebleeding, n (%)
ITT analysis	13 (19.7%)	9 (14.3%)	0.84 (0.56- 1.25)	0.414
PP analysis	10 (20.8%)	5 (22.7%)	1.04 (0.70- 1.55)	0.858
30 days death, n (%)
ITT analysis	2 (3.0%)	1 (1.6%)	0.76 (0.34- 1.73)	0.587
PP analysis	1 (2.1%)	1 (4.5%)	1.38 (0.34-5.58)	0.566
Major cardiovascular events, n (%)
ITT analysis	12 (18.2%)	3 (4.8%)	0.52 (0.43- 0.81)	0.017
PP analysis	6 (12.5%)	2 (9.1%)	0.90 (0.58-1.40)	0.677

ITT, intention-to-treat; PP, per-protocol; HR, hazard ratio; CI, confidence interval

Conclusion

In ischemic heart disease patients who occurred acute upper gastrointestinal bleeding, liberal blood transfusion reduced the hospital stay length, and the events of major cardiovascular events after bleeding. There was no significant difference in the 30-day rebleeding and 30-days all-cause death found between the restrictive and liberal blood transfusion groups.

References

1. Docherty AB, Walsh TS. Anemia and blood transfusion in the critically ill patient with cardiovascular disease. Crit Care.2017,21(1): 61.
2. Gralnek IM, Dumonceau JM. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015 Oct;47(10):a1-46.
3. Sung JJ, Chiu PW. Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018.Gut. 2018 Oct;67(10):1757-1768.
The study is funded by 1·3·5 Project for Disciplines of Excellence–Clinical Research Incubation Project 2020HXFH039, West China Hospital, Sichuan University.

Disclosure

Nothing to disclose.

Introduction

Functional dyspepsia (FD) is associated with duodenal eosinophilia and gut microbiota dysbiosis. Proton pump inhibitors (PPIs), as a first-line therapy, can suppress duodenal eosinophilic inflammation to ameliorate symptoms, yet the symptom relief rate is low. Rifaximin (RIF), an antibiotic known to modulate the gut microbiota, may offer an alternative therapeutic avenue. It is hypothesized that combining RIF with PPIs could more effectively alleviate FD symptoms and duodenal inflammation by targeting the gut microbiota.

Aims & Methods

A single-center, open-label, randomized controlled clinical trial was conducted on subjects who met the inclusion and exclusion criteria (Trial registration: ChiCTR2300069313). Ninety-six patients were randomly assigned in a 1:1 ratio to either the PPI+RIF group or the PPI group. The follow-up period extended to 4 weeks post-treatment cessation. The primary endpoint was the symptom relief rate, while secondary endpoints included symptom response rate, duodenal eosinophil counts, and changes in the microbiota. The study hypothesis was that the clinical efficacy of PPI+RIF would be superior to that of PPI monotherapy.

Results

	PPI+RIF	PPI	Z value	P value	PPI+RIF	PPI	Z value	P value
Abbreviations: PPI+RIF: Proton Pump Inhibitor plus Rifaximin; PPI: Proton Pump Inhibitor; ITT: the intention-to-treat analysis;PP: the per-protocol analysis.
Symptom relief rate	ITT				PP
Week 2	54.2%（26/48）	54.2%（26/48）	0.000	0.500	53.7%（22/41）	53.3%（24/45）	0.030	0.488
Week 4	72.9%（35/48）	58.3%（28/48）	1.522	0.064	76.7%（33/43）	56.8%（25/44）	2.020	0.022
4 weeks post-treatment	77.1%（37/48）	47.9%（23/48）	3.095	0.001	78.6%（33/42）	48.9%（22/45）	3.036	0.001
Symptom response rate	ITT				PP
Week 2	70.8%（34/48）	72.9%（35/48）	-0.227	0.590	68.3%（28/41）	73.3%（33/45）	-0.514	0.696
Week 4	81.3%（39/48）	77.1%（37/48）	-0.503	0.307	83.7%（36/43）	75.0%（33/44）	1.012	0.156
4 weeks post-treatment	85.4%（41/48）	68.8%（33/48）	1.982	0.024	85.7%（36/42）	71.1%（32/45）	1.688	0.046

A total of 96 patients were enrolled in the randomized controlled study. There were no statistically significant differences in baseline demographic data and clinical characteristics between the two groups. According to the intention-to-treat (ITT) analysis, the PPI+RIF group showed significantly higher rates of symptom relief (P = 0.001) and symptom response (P = 0.024) at 4 weeks post-treatment. These findings were supported by the per-protocol (PP) analysis, which revealed a superior symptom relief rate for the combination group at both 4 weeks of treatment (P = 0.022) and 4 weeks post-treatment (P = 0.001), as well as a superior symptom response rate at 4 weeks post-treatment (P = 0.046). Combination therapy also led to a greater reduction in duodenal eosinophil infiltration (P = 0.036) and significantly decreased peak hydrogen sulfide (H₂S) levels (P < 0.001), indicating a reduction in small intestinal bacterial load. Oral microbiota analysis revealed that β-diversity of the oral flora increased following the PPI+RIF intervention, with an increased relative abundance of Enterococcus (P = 0.004). Conversely, the PPI intervention led to the enrichment of the potentially pathogenic bacterium Catonella (P = 0.006). Notably, treatment responders in the PPI+RIF group showed a specific enrichment of the Eubacterium_yurii_group (P = 0.037), an alteration associated with the amelioration of duodenal eosinophilic inflammation and the enhancement of pathways related to preventing bacterial invasion of the epithelium.

Conclusion

In patients with FD, combining a PPI with Rifaximin is superior to PPI monotherapy, improving both symptoms and duodenal eosinophil infiltration. This effect is linked to a reduction in H₂S-producing bacteria and a beneficial shift in the oral microbiota. The oral abundance of Eubacterium_yurii_group may serve as a biomarker for treatment response.

Disclosure

The authors declare that they have no conflicts of interest.