Pharmacologic Options in the Management of UpperGastrointestinal Bleeding: Focus on the ElderlyMoe Htet Kyaw • Francis Ka Leung ChanPublished online: 22 March 2014Springer International Publishing Switzerland 2014

MAUREN LUSI SELFIANA 0961050115

PEMBIMBING : DR. HILDEBRAND HANOCH V. WATUPONGOH, SP.PD

Introduction

Peptic ulcer bleeding is a common and potentially fatal condition

The management of peptic ulcer bleeding has developed in the past two decades with the advent of effective endoscopic hemostasis and potent acid-suppressing agents

This article will review the current pharmacologic treatment options for peptic ulcer bleeding, focusing on the benefits and risks when applied to the elderly population

Peptic Ulcer and Upper Gastrointestinal Bleeding in the Elderly

In the 1970s, the introduction of H2-receptor antagonists (H2RAs) as an anti-secretory therapy reduced the rate of elective surgery for peptic ulcer disease

Two major advances in the treatment of peptic ulcer disease have been introduced, which are proton pump inhibitors (PPIs) and therapy for the eradication of Helicobacter pylori

There are two reasons for the higher incidence of peptic ulcer in elderly patients, the first is the increasing use of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, and the second is the high prevalence of H. pylori infection

In a comparative study by Kemppainen et al. (age[65 vs. B65 years, n = 125), typical epigastric pain in the older age group was rare

In addition, ulcer bleeding was present more commonly in the older age group

Medical Treatment of Upper GastrointestinalBleeding

Endoscopic treatment is the first-line treatment modality for upper gastrointestinal bleeding

After the index endoscopy, re-bleeding occurs in up to 20 % of cases

In the elderly population (age C70 years), the mortality from peptic ulcer bleeding can be as high as 30 %

Medical Therapy Prior to Endoscopy : Erythromycin- Administration of prokinetics prior to endoscopy has been suggested to improve

visualization during endoscopy- A meta-analysis of three published, randomized, controlled trials, and two

published abstracts suggested that intravenous erythromycin or metoclopramide before endoscopy decreased the requirement of a repeat endoscopy

Proton Pump Inhibitors (PPIs)- In the largest of the studies on pre-endoscopy PPI infusion, Lau et al

showed that the need for endoscopic treatment during index endoscopy was lower in the omeprazole group compared with placebo

- A similar result was reported by a meta analysis of six randomized studies suggesting administration of PPIs prior to endoscopy did not improve the rate of re-bleeding

- PPIs did reduce the number of patients showing high-risk stigmata of hemorrhage such as active bleeding, non-bleeding visible vessel, or adherent clot and the requirement of therapy during the index endoscopy

Medical Therapy Post-Endoscopy A meta-analysis of five randomized studies reported that a bolus

followed by continuous infusion of intravenous PPIs (80-mg bolus followed by 80 mg/h for 72 h) compared with placebo had a significant benefit in reducing re-bleeding, surgery, and mortality

From the analysis of two studies comparing intermittent PPI therapy with H2RA, there was no significant difference in re-bleeding, surgery, or mortality

For optimal dosage of PPIs, a recent Cochrane review compared high-dose PPIs with low-dose PPIs for the treatment of bleeding peptic ulcers

The cumulative dose of PPI received within 72 h of treatment: low dose (120 mg or less/72 h), high dose (600 mg or higher/72 h)

With regard to a comparison of oral administration versus intravenous administration of PPIs, a recent meta-analysis of six randomized studies reported no significant differences in re-bleeding, mean volume blood transfused, or requirement of surgery

Thus, in patients with endoscopic features suggesting a low risk of re-bleeding (flat pigment spot, clean base ulcers), oral PPIs would suffice for ulcer healing

Management of Drug-Induced Peptic Ulcer Bleeding

As the use of oral NSAIDs, including cyclo-oxygenase (COX)-2 inhibitors, with aspirin and H. pylori infection are the two main reasons for peptic ulcer bleeding in the elderly Non-steroidal Anti-inflammatory Drugs (NSAIDs): Selective NSAIDs

and Cyclo-oxygenase (COX)-2 Inhibitors - Reports have suggested that the risk of upper gastrointestinal bleeding with

NSAIDs increases with age- Aches and pains are common problems in the elderly, and symptom control

can be challenging, as both anti-inflammatory and opiate drugs can cause adverse effects

- Chan et al. compared a COX-2 inhibitor (celecoxib, 200 mg twice daily) with a non-selective NSAID (diclofenac, 75 mg twice daily), combined with omeprazole in patients who presented with ulcer bleeding (n = 287)

- The mean age of the study population was 66.5 and 66.8 years in the celecoxib group and the diclofenac combined with omeprazole group, respectively

- The probability of recurrent bleeding over a 6-month period was 6.3 % for patients that received celecoxib, and 6.4 % for patients who received diclofenac with omeprazole

- In another study (n = 441, mean age 70 years, 72) by Chan et al., celecoxib (200 mg, twice daily) with esomeprazole twice daily was compared with celecoxib alone

- They reported that combination treatment compared with celecoxib alone resulted in less ulcer bleeding, with a recurrent bleeding rate of 0 and 8.9 %, respectively

- The current consensus among experts suggests that a COX-2-selective NSAID with a PPI is superior to a COX-2 selective inhibitor alone in reducing ulcer bleeding

Aspirin and Clopidogrel

- To investigate the optimal strategy for such cases, a randomized controlled trial (n = 156) by Sung et al. compared continuation (with PPIs) and stopping aspirin therapy in patients with peptic ulcer bleeding

- Although there was an increased risk of rebleeding in the aspirin group (10.3 vs. 5.4 %), there was a reduced risk of all cause mortality (1.3 vs. 10.3 %)

- Patients that are taking dual antiplatelet therapy after the placement of drug-eluting coronary stents are at a higher risk of thrombosis when medications are halted during upper gastrointestinal bleeding

- This was supported by a large prospective study reporting that the strongest predictor of stent thrombosis within 6 months was discontinuation of clopidogrel (hazard ratio 13.74)

- With the current evidence suggesting a high risk of stent thrombosis, after endoscopic control of bleeding, the consensus is that clopidogrel should only be withheld for a short period of time

Strategies for the Prevention of Drug-Induced Ulcer Complications

Prevention of NSAID-Induced Ulcer Complications : PPI for Gastroprotection :

Several studies have shown evidence to support the benefit of short-term treatment (< 3 months) of PPIs to prevent NSAID-induced lesions

Treatment with PPIs resulted in an absolute reduction of peptic ulcer by 36.6 % in short-term NSAID users and 34.6 % in long-term NSAID users

The largest of the randomized studies were VENUS (Verification of Esomeprazole for NSAID Ulcers and Symptoms) and PLUTO (Prevention of Latent Ulceration Treatment Options), both with similar study designs

The VENUS study, the proportion of patients developing ulcers was 4.7%, 5.3%, and 20.4 % while on esomeprazole (40 mg/day, p\0.0001), esomeprazole (20 mg/day, p\0.001), and placebo respectively

In the PLUTO study, the results were 4.4 % with esomeprazole (40 mg/day, p = 0.007), 5.2 % esomeprazole (20 mg/day, p = 0.018), and 12.3 % with placebo

PPI vs. H2-Receptor Antagonists for Gastroprotection A large randomized study (n = 541), ASTRONAUT (acid suppression trial:

Ranitidine versus omeprazole for NSAID-associated ulcer treatment), compared omeprazole (20, 40 mg/day) with ranitidine (120 mg twice daily), in both the treatment and prevention of NSAID-induced ulcers

maintenance therapy of 6 months, 72 % of patients in the omeprazole (20 mg/day) group remained in remission compared with 59 % in the ranitidine group

The study included patients aged 18–85 years of age of 56 in both groups PPI vs. Misoprostol for Gastroprotection

One of the largest studies (n = 935) is OMNIUM (Omeprazole versus Misoprostol for NSAID-induced Ulcer Management), which compared omeprazole (20 mg/day) with misoprostol (400 µg/day) or placebo for 6 months for healing and preventing ulcers associated with NSAIDs

The mean age of patients was 63 and 60 years A higher proportion of patients remained free from peptic ulcers with

maintenance of omeprazole (61 %) compared with misoprostol (48 %, p = 0.001) or placebo (27 %, p\0.001)

Another randomized study (n = 515) that focused more on the elderly population (age [55 years) showed that PPI was superior to misoprostol with a remission rate at 6 months being 95 % (pantoprazole) and 86 % (misoprostol)

Prevention of Aspirin-Induced Ulcer Complications Aspirin is one of the most commonly used NSAIDs in the elderly

population A randomized study (n = 123) recruited patients who had ulcer

complications after low-dose aspirin use After healing of the ulcer, patients were randomized to lansoprazole (30

mg/day) or placebo while remaining on aspirin After a median follow-up of 12 months, ulcer recurrence rate was 14.8

% (placebo) and 1.6 % (lansoprazole) Prevention of COX-2 Inhibitor-Induced Ulcer Complications

Gastrointestinal hemorrhage associated with NSAIDs is due to inhibition of the COX-1 isoform, thus selective COX-2 inhibitors were developed to reduce complications, while maintaining therapeutic efficacy

A large retrospective study (n = 1,383) showed a large risk reduction of upper gastrointestinal complications with a COX-2 inhibitor and PPI treatment strategy

Similar results were reported by the VENUS study with pooled ulcer rates for patients using COX-2 inhibitors of 15.5 % on placebo, 0.9 % on esomeprazole 20 mg, and 4.1 % on esomeprazole 40 mg

Summary for Strategies for Prevention of Drug- Induced Ulcer-Related Complications In elderly patients with co-morbidities and a history of ulcer

complications, finding a safe strategy for NASID use may be difficult If treatment with NSAIDs cannot be avoided, a combination of a COX-

2 inhibitor with a PPI may offer the best gastrointestinal protection

Treatment of H. pylori-Associated Peptic UlcerBleeding The prevalence of H. pylori infection in patients with peptic ulcer aged

over 65 years has been reported to be in the range of 58–78 %

The current consensus for first-line triple therapy treatment for H. pylori eradication includes a twice-daily PPI, together with clarithromycin (500 mg twice daily) and amoxicillin (1 g twice daily) or nitroimidazole (500 mg twice daily) for a minimum of 7 days for all ages

In a prospective study on the cure of H. pylori infection in elderly patients, there was no significant difference in H. pylori eradication between twice-daily PPIs and once-daily PPIs or high-dose (500 mg twice daily) and low-dose (250 mg twice daily) clarithromycin, although prolonged duration of treatment (14 days)

Multi-morbidity, Polypharmacy, and Peptic Ulcer Treatment

Aging is often accompanied by multiple chronic diseases, co-morbidities, disability, frailty, and social isolation

An observational study in the US reported at least 80 % of patients over the age of 75 years to have more than two chronic conditions

For example, a patient admitted to hospital with peptic ulcer bleeding often has chronic diseases, which are risk factors for upper gastrointestinal bleeding (e.g., chronic renal impairment, coronary artery disease)

Multiple diseases and multi-morbidity lead to the use of multiple drugs or polypharmacy

Polypharmacy can be either a risk factor for peptic ulcer bleeding or hinder effective drug therapy for peptic ulcers

The national service framework for older people in the UK recommends regular medication reviews, with patients taking four or more drugs being reviewed every 6 months and those taking fewer reviewed annually

Increasing age is associated with changes in pharmacokinetics and pharmacodynamics affecting the distribution, metabolism, and excretion of drugs

The high prevalence of adverse drug reactions in the elderly is the result of elderly people often being frail and highly sensitive to polypharmacy, with alterations in pharmacokinetic and pharmacodynamic factors and multi-organ dysfunction

The management of upper gastrointestinal bleeding can be challenging in the elderly

There is a significant body of evidence to suggest anti-secretory medications are useful in the treatment of peptic ulcers and their complications in the elderly

It will be important to practice the appropriate use of acid suppression therapy, and identify which patients will gain maximum benefit from PPI therapy

Summary