Standard Triple-Therapy versus

Sequential Therapy for the treatment

of Helicobacter pylori

Heather R Jewell, PA-SDecember 10, 2008

Introduction to Helicobacter pylori1

• Spiral flagellated gram-negative rods

inhabiting gastric mucosa

• H. pylori is associated with gastritis,

peptic ulcer disease and gastric cancer

Introduction2,3

• Over half the world is infected with H.

pylori bacteria

• Acquisition is related to hygiene and

sanitation

• Transmitted via person-to-person, fecal-

to-oral or gastro-to-oral modalities

Introduction:

Clinical Presentation4,5

• Dyspepsia• Anorexia, bloating, belching, regurgitation,

heartburn, epigastric discomfort

• Peptic ulcer disease• Gnawing, dull, aching or hunger-like feeling.

• Relief of pain with food or antacids

• No correlation to food, or a worsening of symptoms

• Gastric cancer• Significant weight loss

• Palpation of a mass

Introduction:

Diagnosis4,5,6

• Endoscopy – Gold Standard 95-99%• Histologically viewed and subjected to rapid urease testing yielding greater

accuracy with the added advantage of performing antibiotic sensitivity tests

• Urea Breath > 95% • The urea breath test takes advantage of the urease enzyme produced by H.

pylori bacteria.

• A patient ingests carbon-labeled urea, which is then hydrolyzed by the bacteria and detected in the breath as labeled CO2.

• Fecal antigen ~ 92%• Tests detect the presence of a polyclonal anti-H. pylori antibodies

• Serology < 90%• Presence of anti-H. pylori antibodies (IgG) in the blood serum indicating

previous exposure rather than current infections.

• Formats include ELISA, immunochromatography and Western blot techniques

Introduction:

Treatment Options

• Double therapy• Proton-pump inhibitor plus antibiotic6

• Triple therapy• Proton-pump inhibitor (PPI), and two antibiotics,

usually clarithromycin and amoxicillin (or an imidazole). 6,7

• Sequential therapy• 5 days of a PPI plus an antibiotic (amoxicillin)

followed by another 5 days of a PPI plus 2 antibiotics (clarithromycin and a 5-nitroimadazole)7,8,9

Purpose & Review Methods

• In adults infected with H. pylori is a sequential treatment regimen more effective than standard triple therapy?

• Library search using Cochran, PUBMED and Medline

• Inclusion Criteria: RCTs, standardized 10-day sequential treatment regimen and either 7, 10 or 14 day standard triple-drug therapies

• Exclusion Criteria: previous treatment, antibiotic substitutions, studies before 1998.

Study 1:Vaira, D., Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication. Annals of Internnal Medicine. 2007;146:556-563.

• Objectives: to compare the efficacy of 10-day sequential treatment with standard 10-day triple therapy in the treatment of Helicobacter pylori

• Methods:• a 10-day sequential therapy regimen or 10-day standard

therapy group

• Measures were taken to conceal the identity of the medications and all patients took 3 medications twice daily for 10 days to ensure blinding.

• Results: Eradication rate using Intention to treat protocols showed the sequential regimen eradicated 93% compared to 79% of the standard treatment.

Study 2Zullo, A., et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther. 2003;17:719-726.

• Objectives: To evaluate eradication outcomes of the 7-day triple therapy compared to a 10-day sequential therapy

• Secondary objectives evaluated adverse effects of both regimens

• Methods:

• 1049 patients, multicenter open-label, randomized, controlled study

• Patients were randomly assigned to a 10-day sequential therapy group or a 7-day standard therapy group

• Results:

• The sequential treatment regimen yielded intention-to-treat eradication rates of 92% compared to 74% of standard therapy

• Minor side effects were reported in 7% of the sequential therapy group and 9% of the standard therapy group.

Study 3Zullo A, Gatta L, De Francesco V, et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment Pharmacol Ther. 2005;21:1419-1424.

• Objectives: To compare the efficacy of a sequential 10-day treatment regimen and a standard 7-day treatment regimen among patients ages 65-83 years old with peptic ulcer.

• Methods:• Multi-center, prospective, open-label, randomized trial

• 179 patients were split into a 10-day sequential therapy or a standard 7-day triple therapy

• Results:• Eradication rates for the sequential regimen were 94.4% at

intention-to-treat compared to 80% ITT for standard triple therapy.

• There were no statistical differences in rates of ulcer healing (95.5 % for sequential vs. 92.2% for standard) or reported adverse effects (10.3% for sequential, 11.5% for standard).

Summary of Results

Study 1a Study 2b Study 3c

Sample Size 300 1049 179

Date of Publication 2007 2003 2005

Study DesignRCT-prospective,

double blind

RCT-prospective

open- label

RCT-prospective

open- label

Intervention

10 day sequential

vs. 10 day standard

therapy

10-day sequential

vs. 7-day standard

therapy

10-day sequential vs.

7-day standard

therapy

Results93% eradication

vs. 79%

92% eradication

vs. 74%

94% eradication vs.

80%

Conclusion

Sequential therapy

had a higher rate of

eradication

Sequential therapy

had a higher rate of

eradication

Sequential therapy

had a higher rate of

eradication

Level of Evidence 1b 1c 1c

a. Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication. Annals of Internal

Medicine. 2007;146:556-563. b. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment.

Aliment Pharmacol Ther. 2003;17:719-726. c. Zullo A, Gatta L, De Francesco V, et al. High rate of Helicobacter pylori eradication with

sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment Pharmacol Ther. 2005;21:1419-1424.

Discussion

• Study 1: Level of evidence 1b• Prospective RCT, double blind

• Data only from Italy

• Study 2: Level of evidence 1c• Large sample size

• Different treatment durations

• Data only from Italy

• Study 3: Level of evidence 1c• Prospective RCT, open label

• Limited age range

• Use of antacids ad libitum

Strengths and Limitations

Strengths

• Useful for primary care

providers looking for a

more effective treatment

of H. pylori

• Surpasses standard 3-

day treatment regimen

• May reduce the overall

cost of treatment due to

primary failure

Limitations

• Cost of four medications

• PCN allergy

• Increased GI side effects

due to 5-nitroimadazole.

• Patient Compliance

• Only for treatment naive

Conclusion

• The three studies reviewed demonstrate

that the sequential treatment regimen

has a higher eradication rate than

standard triple-therapy for the

eradication of H. pylori.

Acknowledgements

• Raymond Eifel MS, PA-C

• Major Advisor

References

• 1. Lauwers GY, Srivastava A. Gastric preneoplastic lesions and epithelial dysplasia. Gastroenterol Clin N Am. 2007;36:813-829.

• 2. Vilaichone R-K, Mahachai V, Graham DY. Helicobacter pyloridiagnosis and management. Gastrointerol Clin N Am. 2006;35:229-247.

• 3. Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76(7):1005-1012.

• 4. Collins J, Ali-Ibrahim A, Smoot DT. Antibiotic therapy for Helicobacter pylori. Med Clin N Am. 2006;90:1125-1140.

• 5. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. An Intern Med. 2008;148:923-931.

• 6. Ables AZ, Simon I, Melton ER. Update on Helicobacter pyloritreatment. Am Fam Physician. 2007;75:351-358.

• 7. Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled data analysis. Gut. 2007;56:1353-1357.

• 8. Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor-based triple therapy for Helicobacter pylori eradication. Ann Intern Med. 2007;147:553-562.

• 9. Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication. Annals of Internal Medicine. 2007;146:556-563.

• 10. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther. 2003;17:719-726.

• 11. Zullo A, Gatta L, De Francesco V, et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment Pharmacol Ther. 2005;21:1419-1424.