e-Newsletter

Perianal Crohn’s disease: moving forward

Mr. Janindra Warusavitarne Consultant Colorectal Surgeon St Mark’s Hospital London, UK

Perianal Crohn’s disease (PCD) continues to be associated with poor disease outcomes and a high patient burden, highlighting the need to assess the current clinical landscape and future strategies.^1,2 Adopting a personalised approach is essential in selecting disease management methods that maximise patient outcomes.

Streamlining the patient pathway can optimise PCD management

An initial publication in the UK highlighted significant delays in treatment due to challenges in the early identification of PCD.³ Variation in symptom presentation can hinder recognition and delay treatment, particularly in cases involving perineal abscesses and fistulas. Focusing on patients with recurring issues or limited wound healing could potentially reduce treatment delays and improve overall effectiveness.

Moreover, taking a multidisciplinary approach is essential in addressing bottlenecks across the entire patient pathway. Joint clinics promote collaboration between gastroenterologists, surgeons and radiologists, educating them on the responsibilities and challenges each role faces. Combining surgical and medical approaches with continuous patient engagement—from diagnosis to treatment to long-term management—is vital in maximising outcomes and quality of life.

Minimise complications by prioritising local treatment

Achieving adequate drainage prior to immunosuppressive therapy is essential to reduce recurrence, prevent infection and improve wound healing.⁴ While setons have shown to be effective, identifying the appropriate timing for their removal is also paramount. 3D reconstruction of MRI scans allows for the visualisation of existing tracts, enabling surgeons to ensure adequate drainage and design effective treatment protocols.⁵

Moreover, local control of the fistula is key to minimising complications, maximising benefits, and reducing rehospitalisation. Preliminary data on video-assisted anal fistula treatment (VAAFT) have shown significant benefits for symptom control, particularly in patient-reported pain and discharge.⁶ Furthermore, studies on advancement flap and lift procedure approaches suggest improved healing rates. This research underscores the importance of local treatment, emphasising the need for new technologies to direct future treatment strategies.

Enhancing outcomes through technology and patient-centric strategies

Stem cell therapies have shown positive results in clinical settings but face various limitations. Allogeneic stem cells lack long term data and require expensive manufacturing and logistical processes, while autologous therapies require additional invasive surgery, extending treatment duration. Notable new directions in the experimental stage involve developing a stem cell-coated fistula plug⁷, autologous platelet-rich fibrin⁸, and therapeutic RNA-encapsulated extracellular vesicles.⁹

Mr. Warusavitarne also contributed to a recent consensus statement developing a PCD patient classification system that categorises PCD patients based on symptom severity.¹⁰ Through this system, doctors hope to take on a more personalised approach, aiming to predict patient outcomes and responses to therapy more accurately, thus maximising quality of life.

References

1. Atia O, et al. Clin Gastroenterol Hepatol 2022;20:e484-e495.
2. Weng MT, et al. Crohns Colitis 360 2023;5:otad035.
3. Lee MJ, et al. Colorectal Dis 2018;20:797-803.
4. Parian AM, et al. Am J Gastroenterol 2023 June 12 [Epub ahead of print].
5. Sahnan K, et al. Ther Adv Gastroenterol 2018;11:175628481877506.
6. Adegbola SO, et al. J Crohns Colitis Published online May 25, 2018.
7. Dozois EJ, et al. Dis Colon Rectum 2019;62:615-622.
8. De La Portilla F, et al. J Gastrointest Surg 2020;24:2814-2821.
9. Mignini I, et al. Cells 2023;13:90.

The grey zone in HBV: should we be treating?

Professor Jordan J Feld Professor of Medicine R. Phelan Chair in Translational Liver Disease Research Toronto Centre for Liver Disease University of Toronto Canada

Hepatitis B virus (HBV) infection is a dynamic disease, characterised by fluctuating serum levels of HBV DNA and alanine aminotransferase (ALT).¹ Antiviral therapy is recommended when both are elevated; however, in grey zone (GZ) patients who exhibit elevated levels of either HBV DNA or ALT, the decision to treat is more challenging.¹ This is further complicated by differing HBV treatment thresholds across various guidelines.¹

Asian patients with HBV are at higher risk²

Current guidelines generally recommend close monitoring for GZ patients, followed by liver biopsy and potential treatment.^3,4 However, this approach may be too conservative, especially for Asian patients, for whom GZ status is more common and is more likely to result in significant histology than inactive or immune tolerant (IT) disease.^1,2 Additionally, despite hepatitis B e antigen-positive (HBeAg+) status being less common than HBeAg-negative (HBeAg-) status in these patients, it is significantly associated with more severe histology (p=0.002).² These findings suggest that Asian patients are at increased risk of adverse outcomes and would likely benefit from earlier antiviral therapy.²

Different GZ patients require tailored treatment strategies

Dr Feld proposed categorising GZ patients into subtypes based on HBeAg status, and serum ALT and HBV DNA levels (Table).⁵ These subtypes are GZ+, GZ- low and GZ- high.⁵

Table. Proposed GZ subtypes and strategies

Close monitoring and/or early antiviral treatment may benefit GZ+ patients. A study comparing noncirrhotic HBeAg+ IT, GZ and immune active (IA) patients found that untreated IT and GZ patients had a significantly higher risk of hepatocellular carcinoma (HCC) and death or liver transplant than treated IA patients (p<0.001).⁶ Interestingly, lower HBV DNA—which reflects the transition from IT to IA disease—was a risk factor for HCC.⁶ Because this transition period may be accompanied by silent progression of fibrosis, liver complications and hepatocarcinogenesis, it may be prudent to initiate antiviral therapy or closely monitor these patients for progression to IA disease, followed by timely treatment (Table).^1,5

Patients with GZ status, especially GZ- high, have a higher incidence of HCC than those with inactive disease.⁷ Furthermore, untreated GZ patients with HBV DNA levels exceeding 2,000 IU/mL are at higher risk of both HCC and death/liver transplant compared with treated IA patients, regardless of ALT levels.⁸ This suggests that treatment decisions based on HBV DNA levels alone may be adequate.⁸ Overall, GZ- low patients should be evaluated for alternative causes of ALT elevation, while early treatment should be considered for GZ- high patients to prevent unnecessary outcomes (Table).^5,8

To conclude, in managing GZ patients, especially those of Asian descent, leaning towards earlier antiviral therapy may help prevent adverse outcomes.⁶

References

1. Mak LY, et al. J Viral Hepat 2024;00:1-9.
2. Wang J, et al. Aliment Pharmacol Ther 2023;57:464-474.
3. Terrault NA, et al. Hepatology 2018;67:1560-1599.
4. Sarin SK, et al. Hepatol Int 2016;10:1-98.
5. Feld JJ. Presented at: 26^th Joint Annual Scientific Meeting; 2024.
6. Kim GA, et al. Gut 2018;67:945-952.
7. Huang DQ, et al. Clin Gastroenterol Hepatol 2022;20:1803-1812.e5.
8. Choi GH, et al. Aliment Pharmacol Ther 2019;50:215-226.

Endoscopic treatment of obesity

Dr. Joyce Wing-Yan Mak Honorary Clinical Assistant Professor The Chinese University of Hong Kong Hong Kong

Early detection and ongoing monitoring of IBD are crucial for selecting effective treatments, achieving long-term recovery and reducing recurrence. While standard colonoscopy procedures provide accurate results, they are costly and highly invasive.¹ Consequently, alternative monitoring methods should be evaluated for their effectiveness in detecting IBD and improving disease management.

Applying biomarker modalities to enhance IBD monitoring

Measuring c-reactive protein (CRP) in blood provides an accurate, cost-effective, point-of-care test for assessing IBD activity.² A post hoc analysis of the ACCENT trial, involving over 500 patients with Crohn’s disease (CD), demonstrated CRP’s predictive ability of CD relapse, remission and sustained response to anti-tumour necrosis factor (anti-TNF) therapy (AUC=0.70 to 0.75).³ Similarly, a meta-analysis on patients with ulcerative colitis (UC) found that elevated CRP levels were significantly associated with a higher risk of colectomy and a lower likelihood of achieving mucosal healing.⁴ Although CRP is beneficial in predicting anti-TNF response, it cannot accurately predict endoscopic remission or differentiate between IBD subtypes. Furthermore, genetic variations and disease presentations can influence CRP levels, leading to false-negative results.⁵

Faecal calprotectin (FC) is an alternative non-invasive monitoring method for IBD that utilises patient stool samples.² Data demonstrates that FC is a strong surrogate marker for endoscopic disease activity, with sensitivity significantly higher than that of CRP (88% vs 49%, respectively).⁶ However, FC struggles with accuracy across different assays as well as intraindividual variability. Additionally, FC levels may rise 2 to 3 months prior to a relapse becoming apparent, indicating the need for multiple stool samples within a shorter timeframe to accurately assess disease activity.⁷

Research is now exploring combination treatments to enhance sensitivity and reliability in disease monitoring and prediction. A multicentre, randomised-controlled phase 3 trial found that combining CRP and FC was superior to FC alone in predicting endoscopic remission after adalimumab treatment, suggesting the potential for biomarkers to play a key role in IBD monitoring.⁸

Advancing the standard of care using novel sensor technologies

Intestinal ultrasound (IUS) has gained interest in clinical practice due to its low costs, non-invasiveness, and rapid availability, particularly when compared to other imaging modalities such as magnetic resonance imaging(MRI) and computed tomography scan(CAT).^1,9 The procedure can be conducted directly in gastroenterology clinics, avoiding additional appointments and enabling real-time treatment changes. IUS has shown reliable assessment of transmural disease activity in patients with CD through parameters such as bowel wall thickness and vascularisation, with responses to ustekinumab detectable as early as four weeks after treatment initiation (Figure).^1,9

Figure. Graphical representation of the bowel wall layers as seen on IUS and key features of active disease
Source: Chavannes M, et al. Clin Gastroenterol Hepatol 2024.⁸
IBD, Inflammatory bowel disease

Although more research is needed for UC applications, IUS has demonstrated promising results in various correlational studies, offering a potential alternative to endoscopic procedures with significantly lower patient burden. Looking forward, this patient-centric approach is being further explored through wearable devices, which aim to predict inflammatory flares through heart rate or sweat-based readings.¹⁰

References

1. Kucharzik T, et al. Front Gastroenterol 2023;2.
2. Turner D, et al. Gastroenterology 2021;160:1570-1583.
3. Cornillie F, et al. Gut 2014;63:1721-1727.
4. Choy MC, et al. Inflamm Bowel Dis 2019;25:1169-1186.
5. Suk Danik J, et al. Ann Hum Genet 2006;70:705-716.
6. Mosli MH, et al. Am J Gastroenterol 2015;110:802-819.
7. Heida A, et al. Inflamm Bowel Dis 2017;23:894-902.
8. Colombel JF, et al. The Lancet 2017;390:2779-2789.
9. Chavannes M, et al. Clin Gastroenterol Hepatol 2024;22:1790-1795.e1.
10. Hirten R, et al. Gastroenterology 2024;166:S-113.

Extended indication of magnetic sphincter augmentation for post-sleeve gastrectomy patients

Dr. Ian Yu-Hong Wong Clinical Assistant Professor Esophageal and Upper Gastrointestinal Surgery The University of Hong Kong Hong Kong

Targeted strategies can help to prevent acid reflux after sleeve gastrectomy

Sleeve gastrectomy is a common bariatric procedure; however, 5.6% of patients who underwent this procedure were observed to have a pooled incidence rate of de novo Barrett’s oesophagitis (95% CI, 3.5–8.8), as well as high risk ratios of hiatus hernia (risk ratio [RR], 2.09) and gastroesophageal reflux disease (GERD) (RR, 3.32).¹

To prevent these complications, the International Society of Diseases of the Esophagus recommends perioperative esophagogastroduodenoscopy (EGDS) and repairing any hiatal hernia larger than 2 cm in patients planning to undergo bariatric surgery.² Postoperatively, lifestyle changes and optimising the use of proton pump inhibitors (PPIs) are advised for patients with GERD.³ Additionally, anti-reflux surgeries may be performed to restore or enhance the function of the lower oesophageal sphincter to prevent acid reflux, by either addressing the increased esophagogastric junction (EGJ) distensibility or correcting a dilated hiatus or hiatus hernia.⁴

Magnetic Sphincter Augmentation (MSA) is a potential solution for GERD symptoms following sleeve gastrectomy

In a prospective study of 100 patients with GERD, the use of sphincter augmentations demonstrated that 64% of patients (95% CI, 54–73) achieved 50% or greater reduction in exposure after one year.⁵ MSA involves laparoscopically placing a fundic-sparing, magnetic antireflux device around the oesophagus at the level of the lower oesophageal sphincter.⁶

In a prospective, multicentre, single-arm observational study of 30 patients, significant improvements were observed 12 months after MSA implantation. Patients reported significant improvements in GERD-HRQL scores (p<0.001), significant reductions in daily PPI usage (p<0.001) and normalisation of the DeMeester score for total acid exposure time  (Figure).⁶

Figure. Percentage of patients who experienced improvements after MSA implantation.

Careful patient selection for MSA implantation is crucial for optimizing outcomes

Patients eligible for MSA following sleeve gastrectomy should have achieved their weight loss goals (preferably with a BMI under 30), not have dilated oesophagus of more than 3 cm and have undergone adequate hiatus hernia repair.⁷ Additionally, identifying eligible patients based on the sleeve morphology (i.e., tubular, dumbbell, upper pouch or lower pouch configurations) may influence the outcomes such weight loss, prolonged nausea, vomiting and GERD symptoms.⁷

Future initiatives, such as the formation of the Asian Foregut Society, will aim to improve treatment strategies and guidelines in Asia through effective multicentre collaborations between surgeons and gastroenterologists.

References

1. Chandan S, et al. Clin Gastroenterol Hepatol 2024;0(0).
2. Visaggi P, et al. Dis Esophagus 2024;37:doae006.
3. Masood M, et al. J Clin Med 2024;13:1246.
4. Tack J, Pandolfino JE. Gastroenterology 2018;154:277-288.
5. Ganz RA, et al. N Engl J Med 2013;368:719-727.
6. Khaitan L, et al. Obes Surg 2023;33:387-396.
7. Grover K, Khaitan L. Dis Esophagus 2023;36(Suppl_1):doad030.

Efficacy of Oral Iron versus Intravenous Iron in acute gastrointestinal bleeding including cirrhotic patients in Hong Kong: A Two-Centre, randomized control trial
(Summary of thesis 2023)

Dr. Chi-Ho Cheung Department of Medicine & Geriatrics Tuen Mun Hospital

Introduction

Acute gastrointestinal bleeding (GIB) is one of the commonest medical emergencies. According to a Hong Kong epidemiological study, a total of 169,699 GIB events were identified from 2009 to 2019¹. Cirrhotic patients are an important subgroup who suffer from GIB; however, they are frequently excluded in clinical trials.

Up to 47.4-82% suffered from iron deficiency anaemia (IDA) after an episode of acute GIB but this is often underdiagnosed and undertreated^2-4. Uncorrected anemia is associated with increased hospitalizations, disability and risk of death⁵. Patients could remain anaemic after transfusion requiring further correction by iron supplements. Oral iron supplements are considered first-line therapy to correct IDA, but their efficacy is often limited by numerous conditions hampering intestinal absorption and intolerance to their dose related gastrointestinal side effects^6,7.

Intravenous iron supplements are safe alternatives and Ferric carboxymaltose (FCM) is an example. Two European randomized control trial had proven efficacy of intravenous FCM against oral iron supplements in patient suffered from acute GIB^{8, 9}. An observational study also demonstrated intravenous FCM is an effective treatment for iron deficiency anaemia in cirrhotic patients who had acute GIB¹⁰.

To our best knowledge, no clinical trials comparing the efficacy of FCM and oral iron supplements had been performed in the Asian population. Therefore, we conducted this first randomized control trial to compare the efficacy of ferric carboxymaltose with oral iron (III) hydroxide polymaltose complex (IPC) in patients, including cirrhotic ones, who suffered from acute GIB of all etiologies in Hong Kong.

Method

Study design

This study is a two-center, single blinded, randomized control trial conducted from 1^st December 2021 to 31^st October 2022. Recruited patients were randomized to receive oral iron (III) hydroxide polymaltose complex (oral group) or intravenous ferric carboxymaltose (IV group) in a 1:1 ratio.

Randomization to treatment arms was done by drawing treatment protocol stored in sealed envelopes prepared by a gastroenterology fellow who was not involved in the recruitment and analysis process. Assessments were performed on the day of treatment started (day 0), on day 14 and day 42 respectively.

During each visit, study subject was assessed for any recurrent bleeding symptoms, presence of anaemic symptoms, side effects during treatment as well as treatment compliance by MMAS-8 questionnaire and pill count for the oral iron supplement arm. A MMAS-8 score greater than 6 or greater than eighty percent of pills consumed was defined as good drug compliance. The reason for non-compliance would be documented. Blood tests for complete blood count, liver and renal biochemistries, aspartate transaminase (AST), calcium phosphate level, iron profile (include iron, total iron binding capacity and transferrin saturation), ferritin and C reactive protein (CRP) were performed at baseline and during each visit. Baseline iron profile and ferritin values were obtained before any commencement of blood product transfusion. Quality of life assessment of patients were performed by EQ-5D-5L questionnaire at baseline and during each assessment.

Patients were not allowed to take nutritional supplements and traditional Chinese medicine during the 42 days study period. Pack cells transfusion was allowed during the study period upon discretion of the attending physician according to the patients’ clinical needs.

Patient Recruitment

Patients who are above age of eighteen presented to medical or surgical units of Tuen Mun Hospital or Pok Oi Hospital with overt gastrointestinal bleeding symptoms (including coffee ground vomiting, haematemesis, melena or haematochezia) and anaemia, defined as haemoglobin level less than 11g/dL, were eligible for recruitment. Cirrhotic patients with a normal baseline haemoglobin within 6 months prior to admission were also included. Exclusion criteria included conditions predisposing anaemia development, conditions leading to malabsorption, chronic anaemia, consuming nutritional supplements, failing to complete EQ-5D-5L questionnaire and clinical condition changes, details presented in List 1.

Data collected from those excluded due to clinical condition changes would still be counted in the final statistical analysis.

This study was approved by the research ethics committee of the Hospital Authority of Hong Kong. An informed consent must be signed by patients who were included in this study.

List 1. Exclusion Criteria of patients recruitment

Treatment Regimens

Patients in oral group would be given 200 mg of IPC (two Ferrum Hausmann® 100mg chewable tablets, each contained approximately 100mg of elemental iron) once per day in alternate day for a total of 42 days. Patients in the IV group would be given intravenous FCM with dosage determined by their haemoglobin level and body weight on recruitment as shown in Table 1.

Table 1. Dosing of intravenous FCM

Outcome measurement

The primary outcome of the study is normalization of haemoglobin at Day 42 (13g/dL in men; 12g/dL in women¹¹).

Secondary outcomes included partial haemoglobin response (raised for 2g/dL from baseline), rate of rise of haemoglobin, iron store repletion (defined as ferritin level >100 pmol/L if CRP was less than 5mg/L¹²; transferrin saturation greater than 16% if CRP higher than 5mg/L¹³). Adverse events were considered treatment related if they were described in the drug insert and was chronologically related to drug administration. Quality of life measurements were performed by analyzing EQ-5D-5L questionnaire results.

Statistical Analysis

Assuming the effect of intravenous FCM versus oral IPC on normalizing haemoglobin is 100% versus 61%, according to a previous study by Ferrer et al⁹, using confidence interval of 95%, expected power of 90% and expected loss of follow up in 15%, the calculated sample size was 17 patients in each treatment arm.

Statistical analysis was done by IBM SPSS statistics software version 25. The collected data were analyzed by intention to treat approach. Chi square test or Fisher exact test were applied for categorical variables. Mean value, standard deviation was calculated followed by applying independent sample t test or two sampled t test for quantitative parametric variables. Mean ranks were calculated followed by applying Mann Whitney U test or Wilcoxon Signed Rank test for quantitative non-parametric variables.

Results

Patient characteristics

Figure 1 summarized the recruitment details of the study. Eventually 38 patients were enrolled with 19 assigned to each group. Seventeen out of 19 patients in oral group and 16 out of 19 in IV group completed the assigned treatment. Reasons not completing the treatment were described in Figure 1 as well.

Baseline demographic data were summarized in Table 2 with no significant difference between the groups. Majority of the patients had upper gastrointestinal etiology (n=34, 89.4%), commonest due to peptic ulcer disease (n= 23, 65.7%). Four (10.6%) patients had lower gastrointestinal bleeding. Four (10.6%) patients had cirrhosis. The baseline haemoglobin level was 6.66 +/- 1.73 g/dL versus 7.35 +/- 1.61 g/dL in the IV group and oral group respectively. 11 patients in IV group (57.9%) and 10 patients in oral group (52.6%) received pack cell transfusion (1.05 +/- 1.02 units and 0.94 +/- 1.26 units respectively). 63.2% IV group and 52.6% oral group patient had iron deficiency.

Figure 1. Study Design and Outcomes

Table 2. Baseline Characteristics

Abbreviation: BW = body weight, CRP = C reactive protein, FCM = ferric carboxymaltose, GI = gastrointestinal, Hb = haemoglobin, IPC = iron (III) hydroxide polymaltose complex, IQR = interquartile range, NASID = non steroid anti-inflammatory drugs, PO4 = phosphate, PPI = proton pump inhibitor, SD = standard deviation

Efficacy outcomes

Figure 2 summarizes the haemoglobin response in both treatment groups. Significantly larger proportion of patients in IV group achieved the primary outcome than patients in oral group (63% vs 10.5%, p=0002). Patients in both treatment groups achieved significant haemoglobin rise at day 14 and day 42 while comparing to their baseline level, where mean haemoglobin in IV group was significantly higher than oral group at both day 14 (11.35+/-1.25 g/dL vs 9.53 +/-1.57 g/dL, p=0.001) and day 42 (13.73+/-1.18g/dL vs 10.52+/-1.85 g/dL, p<0.00001). The rate of haemoglobin rise was also significantly higher in IV group compared to those in oral group at both day 14 (2.34 vs 1.11 g/dL/week, p<0.00001) and day 42 (1.16 vs 0.53 g/dL/week, p<0.00001). More patients in IV group achieved partial haemoglobin response than those in oral group at day 42, although it did not achieved statistically significance (100% vs 73.7%, p=0.125). There was a larger numeric drop in proportion of patients reporting anaemic symptoms from baseline to day 14 (IV group: 15.8% less, oral group: 10.6% more) and from day 14 to day 42 (IV group:36.8% less, oral group 21.1% less) respectively, yet the difference in change between two groups was not statistically significant (baseline to day14: p=0.607; day 14 to day 42 p= 0.458). In cirrhotic patients, those in IV group showed a mean rate of rise of haemoglobin of 5.1 and 1.08 g/dL/week at week 2 and week 6 respectively, which was comparable with non- cirrhotic patients, although meaningful statistical analysis was not possible due to the limited sample size of cirrhotic patients.

Figure 2. Hb change (A) Rate of Hb change after iv Ferinject and po Ferrum Hausmann over duration of study. Complete (C) and Partial Hb Response (D) after iv Ferinject and po Ferrum Hausmann over duration of study

A

B

C

D

Serum biochemistries and iron availability

Mean ferritin level was significantly higher for patients in IV group compared to oral group at day 14 and day 42 (p<0.0001 respectively) The mean iron saturation was also significantly higher in the IV group at day 14 and day 42 (p<0.0001). Figure 3 and Table 3 summarize the details of efficacy outcomes, the change in blood biochemistries and iron indices after treatment respectively.

Figure 3. Change in Ferritin (A), Iron Saturation (B) after administration of IV FCM and oral IPC over study period

Table 3. Comparison of Outcome Measurement (Intention to treat analysis)

Quality of life outcome

All patients participated in the study completed EQ-5D-5L questionnaire at baseline, day 14 and day 42. At day 14, patients in IV group showed significant improvement in pain/discomfort (p=0.036) and anxiety/depression dimension (p=0.015); while patients in oral group had significant improvement in self-care dimension (p=0.025). At day 42, patients in IV group had significant improvement in their usual activity (p=0.024) and pain/anxiety score (p=0.017); while patients in oral group had significant improvement in the usual activity dimension (p=0.033) as compared to their baseline. Patients in IV group had higher rise in their mean visual analog scale score at both day 14 and day 42 than those in the oral group although not reaching statistical significance (Day 14: 12.81+/-16.83 vs 8.23+/-15.1 points, p=0.307; Day 42 19.62+/-19.98 vs 12.18+/-14.76 points, p=0.188). Figure 4 showed a graphic representation of the change in quality-of-life measurements during the study period.

Figure 4. Change of (A) Mobility; (B) Self-Care; (C) Usual Activity; (D) Pain/Discomfort; (E) Anxiety/Depression; (F) EQ-VAS in patients receiving treatment over time.

A

B

C

D

E

F

Safety outcome

None of the patient experienced allergy to the two studied drugs. In patients received IV FCM, 10 (43.5%) developed hypophosphatemia: 2 (10.5%) mild degree, 9 (36.8%) moderate degree. The mean phosphate level drops from 1mmol/L at baseline to 0.81mmol/L at day 14 then raised to 0.92 mmol/L at day 42. Only 18.8% of patients had their phosphate level normalized at day 42 if they developed hypophosphatemia at day 14, although 81.3% of them had a mean phosphate rise of 0.14+/-0.24 mmol/L. None of the patients developed hypophosphatemia related symptoms nor severe hypophosphatemia that required phosphate replacement. Figure 5 shows the trend of phosphate change after treatment.

Figure 5. Change of Phosphate level after treatment over time

Four (21%) patients experienced transient flushing and rash during IV FCM infusion. One of them developed urticaria one day after IV FCM infusion which may represent delayed onset hypersensitivity reaction. No patient developed moderate to severe hypersensitivity reaction. No additional management was needed for the adverse events. Eleven (57.9%) oral group patients had at least one gastrointestinal side effect. Table 4 summarized the adverse event profile of our studied patients.

Table 4. Summary of Adverse Events

Treatment Adherence

In the IV group, 18 patients (94.7%) completed all planned dose of drug. The non-compliance patient refused the second dose of IV FCM because of experiencing transient urticaria after the first dose. In the oral group, 18 patients (94.7%) reported good compliance, however pill count was successfully performed in 11 patients (61.1%) only. The non-compliance patient self-stopped treatment due to experiencing dark stool after treatment.

Discussion

Efficacy comparison between intravenous and oral iron supplement

Our study showed administration of IV FCM led to a significantly higher rate of haemogloblin normalization (63.2 vs 10.5%), a doubled haemoglobin rising rate (2.34 vs 1.11 g/dL per week over first 2 weeks and 1.16 vs 0.53 g/dL per week over 6 weeks) and a higher likelihood of normalized bodies’ iron store (78.9 vs 21.1%) at day 42 while compared to oral IPC.

Despite the promising results, the efficacy of both intravenous and oral iron supplement to achieve haemoglobin normalization appeared poorer while compared with Ferrer-Barcelo’s study (100 vs 63.2% in IV group; 61 vs 10.5% in oral group). We believed the lower baseline haemoglobin level in our patient groups compared to those in Ferrer-Barcelo’s study (6.66 vs 9.4 g/dL in IV FCM group; 7.35 vs 9.7 g/dL in oral iron supplement group) could be an explanation. Of note, in our IV group patients who could not achieve the primary study outcome, they only failed in a borderline manner. Indeed, all of them had a haemoglobin level within 1g/dL from the defined normal range on day 42. We believed these observations reflect the effectiveness of IV FCM in improving IDA due to GIB in real life settings despite an apparent lower than expected efficacy shown in this study.

Safety of Ferric Carboxymaltose

In our IV group patients, 43.5% patients developed asymptomatic hypophosphatemia. Only 33.3% of patients in our study who had hypophosphatemia in week 2 had normalized phosphate level in week 6. This pinpoints the importance of monitoring to detect persistent hypophosphatemia after patients receiving IV FCM. We propose clinical follow up with serum phosphate level monitoring 2 weeks after patients receiving IV FCM, followed by periodic blood test every three to four weeks to monitor patient’s phosphate level until their serum phosphate level was normalized.

10.3% patients received IV FCM developed mild HSR and did not require medical intervention. Although serious infusion reaction appeared to be rare (0.7-1.7%) in IV FCM, it could progress from initial mild symptoms and could be fatal. Therefore, well trained staff with standardized protocol on complication detection, immediate management, as well as adequate monitoring time before discharging patient after receiving intravenous iron are important safety measures for FCM administration.

Quality of life comparisons

There were a larger numeric and categorical improvements in the IV group patients, in terms of the EQ-VAS score (19.63 vs 12.18 points, 95% C.I -3.83,18.73) and individual dimensions, especially in pain/anxiety (52.6 vs 26.3 %), although not reaching statistical significance. We believe this ‘insignificance’ was related to the smaller sample size in our study rather than truly no difference in view of a wide confidence interval. Other possible causes of the insignificant difference were patients’ occupation, demand on physical activity and lifestyle were not considered and adjusted in our study, which may cause reporting bias to the results.

Strength and Limitation of study

A strength of our study was the randomized control study design using intention to treat analysis. This greatly reduced bias in outcome analysis and is more reflecting the real-world setting.

Another strength of our study was the inclusion of quality-of-life analysis, enabling us to gain insight on effects of different iron supplements improving patients’ quality of life besides the objective laboratory parameters, which composite an important component of health assessment.

There were some limitations in our study. Firstly, patients mentally not capable of answering EQ-5D-5L questionnaire were excluded. These were mainly elderly patients compositing a large population commonly suffer from gastrointestinal bleeding in real life, which may cause selection bias towards a healthier study population. Besides, the sample size of our study was relatively small. Some of the analysis of secondary outcomes (e.g. quality of life outcomes) may be again underpowered and results might not be generally applicable to the entire Hong Kong population. Current data is not sufficient to perform meaningful logistic regression analysis to look for factors predicting success or failure of therapy.

Future research directions and implications of study

Future multicenter trials including different hospitals with larger number of patients are required to draw more concrete conclusion on the efficacy of IV FCM over oral iron supplement, especially on areas such as quality of life improvements and factors predicting success of therapy. Subgroup analysis addressing effectiveness of IV FCM on different GIB etiologies and cirrhotic patients could also be performed, given our study showed numerically promising improvements in haemoglobin in these patient groups. Cost effectiveness analysis is essential to evaluate whether it is financially sound to use IV FCM as the first line treatment for these patients (approximate $1500-2000/course of FCM vs $ 135 per course of oral IPC).

We are in an era of frequent shortage of blood products. Our study findings could imply potential of avoiding transfusion in healthier patients with borderline haemoglobin level (e.g. Haemoglobin level of 6-7 g/dL) after acute gastrointestinal bleeding. Further studies are needed to determine the tightened threshold of transfusion trigger as well as the acceptable level of patient comorbidity where such practice would not hamper patient’s safety.

Conclusion

This study showed IV FCM is an effective treatment in correcting iron deficiency anaemia in patients suffered from acute gastrointestinal bleeding and is superior to oral iron therapy in terms of a more rapid rise of haemoglobin and normalization of body’s iron store. This treatment is generally safe and severe adverse reactions are rare, however particular attention should be paid to detect and manage hypophosphatemia after patient receiving this drug.

Reference

1. Guo CG, Zhang F, Wu JT, Cheung KS, Li B, Law SYK, et al. Divergent trends of hospitalizations for upper and lower gastrointestinal bleeding based on population prescriptions of aspirin, proton pump inhibitors and Helicobacter pylori eradication therapy. United European Gastroenterology Journal. 2021;9(5):543-51.
2. Mearin F. Vivir sin anemia. Gastroenterología y Hepatología. 2018;41(4):223-5.
3. Bager P, Dahlerup JF. Lack of follow-up of anaemia after discharge from an upper gastrointestinal bleeding centre. Dan Med J. 2013;60(3):A4583.
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