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Study Overview
Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.
Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).
Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.
Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.
Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.
Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.
There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).
The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).
Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.
Commentary
Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].
The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].
The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.
Applications for Clinical Practice
Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication. Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.
—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN
1. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. Accessed 22 Feb 2014 at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx..
2. SEER Stat fact sheets: stomach cancer. Bethesda, MD: National Cancer Institute. Accessed 22 Feb 2014 at http://seer.cancer.gov/statfacts/html/stomach.html.
3. De Martel C. Gastric cancer: epidemiology and risk factors. Gastroenterol Clin North Am 2013;42:219–40.
4. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterology 2007;102:1808–25.
5. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastrict IV/Florence Consensus Report. Gut 2012;61:646–64.
6. O’Connor A, Molina-Infante J, Gisbert JP, O’Morain C. Treatment of Helicobacter pylori infection 2013. Helicobacter 2013;18(Suppl 1):58–65.
Study Overview
Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.
Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).
Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.
Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.
Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.
Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.
There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).
The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).
Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.
Commentary
Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].
The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].
The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.
Applications for Clinical Practice
Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication. Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.
—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN
Study Overview
Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.
Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).
Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.
Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.
Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.
Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.
There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).
The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).
Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.
Commentary
Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].
The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].
The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.
Applications for Clinical Practice
Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication. Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.
—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN
1. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. Accessed 22 Feb 2014 at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx..
2. SEER Stat fact sheets: stomach cancer. Bethesda, MD: National Cancer Institute. Accessed 22 Feb 2014 at http://seer.cancer.gov/statfacts/html/stomach.html.
3. De Martel C. Gastric cancer: epidemiology and risk factors. Gastroenterol Clin North Am 2013;42:219–40.
4. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterology 2007;102:1808–25.
5. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastrict IV/Florence Consensus Report. Gut 2012;61:646–64.
6. O’Connor A, Molina-Infante J, Gisbert JP, O’Morain C. Treatment of Helicobacter pylori infection 2013. Helicobacter 2013;18(Suppl 1):58–65.
1. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. Accessed 22 Feb 2014 at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx..
2. SEER Stat fact sheets: stomach cancer. Bethesda, MD: National Cancer Institute. Accessed 22 Feb 2014 at http://seer.cancer.gov/statfacts/html/stomach.html.
3. De Martel C. Gastric cancer: epidemiology and risk factors. Gastroenterol Clin North Am 2013;42:219–40.
4. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterology 2007;102:1808–25.
5. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastrict IV/Florence Consensus Report. Gut 2012;61:646–64.
6. O’Connor A, Molina-Infante J, Gisbert JP, O’Morain C. Treatment of Helicobacter pylori infection 2013. Helicobacter 2013;18(Suppl 1):58–65.