Clinical Management of H. pylori Dig Dis 2014;32:281–289 DOI: 10.1159/000357859
Clinical Management of Helicobacter pylori – The Japanese Perspective Kentaro Sugano Hiroyuki Osawa Kiichi Satoh Department of Medicine, Jichi Medical University, Shimotsuke, Japan
Abstract Background: After the approval of health insurance coverage of eradication therapy for Helicobacter pylori-positive peptic ulcer disease (PUD) in 2000, comprehensive coverage for H. pylori infection itself was implemented in 2013. Methods: We did a literature search using PubMed database on the management of H. pylori infection including indications, regimens, outcomes of current eradication therapies, trends of antibiotic resistance rates and proposed third-line rescue therapy in Japan. We also collected data on changes of eradication rates in our hospital by searching electronic medical records. Results: After implementation of insurance coverage of eradication therapy for PUD, dramatic reduction of the number patients with PUD as well as spending on ulcer drug was documented. According to the current regulation, proton pump inhibitor (PPI)-based triple therapy with 2 antibiotics, amoxicillin (AMPC) plus clarithromycin, for 7 days is approved as the first-line therapy. After failure of the firstline therapy, PPI plus AMPC and metronidazole is authorized as the second line, which maintains an excellent eradication
© 2014 S. Karger AG, Basel 0257–2753/14/0323–0281$39.50/0 E-Mail [email protected] www.karger.com/ddi
rate of over 90% in Japan. When these two therapies fail, a sitafloxacin-based therapy seems to be most promising among many rescue regimens. Conclusion: Comprehensive public health insurance coverage of H. pylori infection will promote eradication in Japanese people infected with H. pylori, whose risk of developing gastric cancer has been shown to be high. It also provides us a unique opportunity to study whether the broader indications can accelerate the reduction of gastric cancer in Japan in the same way we witnessed the reduction of PUD. © 2014 S. Karger AG, Basel
Introduction
In Japan, the prevalence of Helicobacter pylori infection in the younger generation has markedly decreased, whereas it remains high (>50%) in the elderly population [1, 2]. This elderly population is also the group at high risk of developing ulcer and gastric cancer. Since it has been well documented that eradication therapy can reduce recurrence of peptic ulcer disease (PUD) [3, 4] and gastric cancer after endoscopic therapy [5, 6], eradication therapy for these indications has been approved for reimbursement by health insurance. Since then, a dramatic reduction of Kentaro Sugano, MD, PhD Department of Medicine, Jichi Medical University 3311-1 Yakushiji Shimotsuke 329-0498 (Japan) E-Mail sugano @ jichi.ac.jp
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
Key Words Helicobacter pylori · Eradication therapy · Antibiotic resistance · Gastric cancer · Peptic ulcer
Approval of eradication therapy
1,400 1,200 1,000
600 400
0
PUD Gastritis/duodenitis
400
800
300 200 100
200
a
Approval of eradication therapy
500
Billion yen
Patients (×103)
600
Total M F
1993
1996
1999
2002
2005
2008
b
0
1985
1990
1995
2000
2005
2008
Fig. 1. Changes in the number of peptic ulcer patients (a) and medical spending on ulcer drugs and gastritis drugs (b). These figures were depicted based on the data from the Journal of Health & Welfare Statistics by the Health & Welfare Statistics Association (a) and Health Statistics by the Ministry of Health Labor and Welfare, Japan (b).
282
Dig Dis 2014;32:281–289 DOI: 10.1159/000357859
Method A literature search using PubMed database was conducted with the search terms Helicobacter pylori and Japan, in combination with epidemiology, eradication therapy and/or triple therapy, or antibiotic resistance between the years 2001 and 2013. Full papers written in English were screened, and relevant papers were selected. Recursive search was also performed from the references of selected papers. Studies in Japanese were also cited, if necessary. We also surveyed the results of eradication therapy using standard first-line triple therapy, proton pump inhibitor (PPI) + amoxicillin (AMPC) + clarithromycin (CAM) conducted in our hospital by searching electronic medical records from 2009 to 2012. In case of failure of the first-line therapy, the results of second-line therapy using metronidazole (MNZ) in place of CAM were also collected. Successful eradication was confirmed by 13C-urea breath tests using 2.5‰ as a cutoff or stool antigen tests after 4–8 weeks of completion of therapy.
Results
Eradication Regimens Eradication using lansoprazole-based triple therapy for H. pylori-positive PUDs (including ulcer scar) was approved for reimbursement by public health insurance in October 2000, based on the clinical trial data showing satisfactory eradication rate [9]. Since then, eradication regimens using other PPIs (omeprazole and rabeprazole) were approved. All three regimens showed similar eradication rates [10–12] ranging from 80 to 90%. The latest addition of PPI-based triple therapy was esomeprazoleSugano/Osawa/Satoh
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
patients with PUD as well as market sales of ulcer drugs was demonstrated (fig. 1). To further reduce the incidence gastric cancer in which H. pylori infection was shown to be a major factor in Japan [7], Japanese Society for Helicobacter Research (JSHR) published a revised guideline according to which H. pylori infection should be treated irrespective of the disease phenotypes such as PUDs or MALT (mucosa-associated lymphoid tissue) lymphoma [8]. Based on the guideline, JSHR, Japanese Society of Digestive Endoscopy and Japanese Society of Gastroenterology jointly made a request to the government to approve insurance coverage for H. pylori-positive gastritis. These efforts come to fruition in February 2013, and all H. pylori infections can now be managed under coverage of public health insurance. The only condition for the reimbursement is to take an upper endoscopic examination before eradication to rule out the active PUD or neoplastic lesions requiring specific care. This policy is quite meaningful since it allows the ‘scope, test and treat’ strategy for H. pylori infection as a package and will be beneficial for patients enabling simultaneous secondary prevention (early detection of cancer and treatment) and possible primary prevention for gastric cancer by eradication. In this review, we summarize the progress in the management of H. pylori infection that has taken place since the approval of H. pylori eradication therapy in 2000 in Japan. In several points, it has notable differences from the standard management of H. pylori infection in Western guidelines.
Table 1. PPI-based triple therapy approved for H. pylori eradication as the first-line regimen
Regimen
PPI and dose
AMPC
CAM
Eradication rate, % Ref.
LAC400
lansoprazole, 30 mg b.i.d.
750 mg b.i.d.
200 mg b.i.d.
LAC800
lansoprazole, 30 mg
750 mg b.i.d.
400 mg b.i.d.
OAC400 OAC800 RAC400 RAC800 EAC800
omeprazole, 20 mg b.i.d. omeprazole, 20 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d. esomeprazole, 20 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
200 mg b.i.d. 400 mg b.i.d. 200 mg b.i.d. 400 mg b.i.d. 400 mg b.i.d.
87.5 (GU) 91.1 (DU) 89.2 (GU) 83.7 (DU) 81.1 80.0 86 89 84*
[9]
[11] [12] [13]
GU = Gastric ulcer; DU = duodenal ulcer. Eradication rates were ITT data except for EAC 800 study [13], in which it was not described whether the eradication rates were ITT or PP (per protocol) data. All the regimens are approved for a period of 7 days. * In this study, no descripiton was given whether the results were based on ITT or PP.
Indications and Guidelines Eradication therapy for H. pylori PUD was approved for public health coverage at the end of 2000. In accord with the government policy, JSHR strongly recommended eradication therapy for H. pylori-positive peptic ulcers [15]. Furthermore, the Japanese clinical guideline for gastric ulcer [16] placed eradication therapy as the first-line therapy for H. pylori-positive ulcers. In addition to this indication, a number of observational studies demonstrated that H. pylori eradication could bring about regression of H. pylori-positive MALTlymphoma patients without chromosomal abnormalities [17, 18]. JSHR, therefore, made a minor revision of the H. pylori Management in Japan
Diagnosis of gastritis by upper GI endoscopy (EGD)
Diagnosis of H. pylori infection (RUT, UBT, SAT, etc.) First-line triple therapy for 7 days (PPI + AMPC + CAM)
Failure
Cure
Second-line triple therapy for 7 days (PPI + AMPC + MNZ)
Failure
Cure
Third-line rescue therapy (arbitrary, not covered by insurance)
Fig. 2. Flow diagram of eradication program for H. pylori infection
according to the government regulation. Framed procedures and treatments are covered by health insurance. EGD = Esophagogastroduodenoscopy; RUT = rapid urease test; UBT = urea breath test; SAT = stool antigen test.
guideline [19] for the management of H. pylori in which MALT lymphoma was categorized into ‘strongly recommended for eradication’ criteria in addition to PUD. Eradication therapies were shown to exert beneficial effects on additional conditions such as metachronous gastric cancer occurrence after endoscopic treatment [5], Dig Dis 2014;32:281–289 DOI: 10.1159/000357859
283
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
based regimen approved through public knowledgebased application (PKBA) without clinical trial in 2011. Thus, only limited results of esomeprazole-based eradication therapy are available in Japan [13] (table 1). It should be noted that in all these regimens, the approved doses of both antibiotics were lower than those used in the Western regimens [14]. In most institutions, CAM 400 mg per day is preferred over 800 mg because of better tolerability. A second-line treatment using MNZ (250 mg, b.i.d.) instead of CAM was also approved in 2007 through PKBA in the face of declining eradication rate with the first-line regimen in the real clinical setting. This regimen (PPIAM) is only permitted when the first-line therapy has failed. The two regimens are used in the sequential manner, and the current flow of H. pylori management according to the health insurance regulation in Japan is shown in figure 2.
Table 2. Results of eradication therapy with PPI, AMPC and MNZ in Japan
Regimen
PPI
AMPC
MNZ
Duration, days
Eradication rate, %
Ref.
LAM
lansoprazole, 30 mg b.i.d. lansoprazole, 30 mg b.i.d. lansoprazole, 30 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d.
7 10 7
96.2 93.7 91.1
27 28 30
OAM
omeprazole, 20 mg b.i.d. omeprazole, 20 mg b.i.d.
500 mg t.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d.
10 7
84.5 90.9
28 30
RAM
rabeprazole, 20 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d.
7 7 7 7
88 82 92.4 91.4
25 26 29 30
Eradication rates are expressed as intention-to-treat-based data.
Current Status of Eradication Therapy As shown in previous sections, the first-line regimens demonstrated satisfactory eradication rates in the clinical trials [9–12]. However, a gradual decline in the eradication rate with this regimen (
Clinical Management of Helicobacter pylori – The Japanese Perspective Kentaro Sugano Hiroyuki Osawa Kiichi Satoh Department of Medicine, Jichi Medical University, Shimotsuke, Japan
Abstract Background: After the approval of health insurance coverage of eradication therapy for Helicobacter pylori-positive peptic ulcer disease (PUD) in 2000, comprehensive coverage for H. pylori infection itself was implemented in 2013. Methods: We did a literature search using PubMed database on the management of H. pylori infection including indications, regimens, outcomes of current eradication therapies, trends of antibiotic resistance rates and proposed third-line rescue therapy in Japan. We also collected data on changes of eradication rates in our hospital by searching electronic medical records. Results: After implementation of insurance coverage of eradication therapy for PUD, dramatic reduction of the number patients with PUD as well as spending on ulcer drug was documented. According to the current regulation, proton pump inhibitor (PPI)-based triple therapy with 2 antibiotics, amoxicillin (AMPC) plus clarithromycin, for 7 days is approved as the first-line therapy. After failure of the firstline therapy, PPI plus AMPC and metronidazole is authorized as the second line, which maintains an excellent eradication
© 2014 S. Karger AG, Basel 0257–2753/14/0323–0281$39.50/0 E-Mail [email protected] www.karger.com/ddi
rate of over 90% in Japan. When these two therapies fail, a sitafloxacin-based therapy seems to be most promising among many rescue regimens. Conclusion: Comprehensive public health insurance coverage of H. pylori infection will promote eradication in Japanese people infected with H. pylori, whose risk of developing gastric cancer has been shown to be high. It also provides us a unique opportunity to study whether the broader indications can accelerate the reduction of gastric cancer in Japan in the same way we witnessed the reduction of PUD. © 2014 S. Karger AG, Basel
Introduction
In Japan, the prevalence of Helicobacter pylori infection in the younger generation has markedly decreased, whereas it remains high (>50%) in the elderly population [1, 2]. This elderly population is also the group at high risk of developing ulcer and gastric cancer. Since it has been well documented that eradication therapy can reduce recurrence of peptic ulcer disease (PUD) [3, 4] and gastric cancer after endoscopic therapy [5, 6], eradication therapy for these indications has been approved for reimbursement by health insurance. Since then, a dramatic reduction of Kentaro Sugano, MD, PhD Department of Medicine, Jichi Medical University 3311-1 Yakushiji Shimotsuke 329-0498 (Japan) E-Mail sugano @ jichi.ac.jp
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
Key Words Helicobacter pylori · Eradication therapy · Antibiotic resistance · Gastric cancer · Peptic ulcer
Approval of eradication therapy
1,400 1,200 1,000
600 400
0
PUD Gastritis/duodenitis
400
800
300 200 100
200
a
Approval of eradication therapy
500
Billion yen
Patients (×103)
600
Total M F
1993
1996
1999
2002
2005
2008
b
0
1985
1990
1995
2000
2005
2008
Fig. 1. Changes in the number of peptic ulcer patients (a) and medical spending on ulcer drugs and gastritis drugs (b). These figures were depicted based on the data from the Journal of Health & Welfare Statistics by the Health & Welfare Statistics Association (a) and Health Statistics by the Ministry of Health Labor and Welfare, Japan (b).
282
Dig Dis 2014;32:281–289 DOI: 10.1159/000357859
Method A literature search using PubMed database was conducted with the search terms Helicobacter pylori and Japan, in combination with epidemiology, eradication therapy and/or triple therapy, or antibiotic resistance between the years 2001 and 2013. Full papers written in English were screened, and relevant papers were selected. Recursive search was also performed from the references of selected papers. Studies in Japanese were also cited, if necessary. We also surveyed the results of eradication therapy using standard first-line triple therapy, proton pump inhibitor (PPI) + amoxicillin (AMPC) + clarithromycin (CAM) conducted in our hospital by searching electronic medical records from 2009 to 2012. In case of failure of the first-line therapy, the results of second-line therapy using metronidazole (MNZ) in place of CAM were also collected. Successful eradication was confirmed by 13C-urea breath tests using 2.5‰ as a cutoff or stool antigen tests after 4–8 weeks of completion of therapy.
Results
Eradication Regimens Eradication using lansoprazole-based triple therapy for H. pylori-positive PUDs (including ulcer scar) was approved for reimbursement by public health insurance in October 2000, based on the clinical trial data showing satisfactory eradication rate [9]. Since then, eradication regimens using other PPIs (omeprazole and rabeprazole) were approved. All three regimens showed similar eradication rates [10–12] ranging from 80 to 90%. The latest addition of PPI-based triple therapy was esomeprazoleSugano/Osawa/Satoh
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
patients with PUD as well as market sales of ulcer drugs was demonstrated (fig. 1). To further reduce the incidence gastric cancer in which H. pylori infection was shown to be a major factor in Japan [7], Japanese Society for Helicobacter Research (JSHR) published a revised guideline according to which H. pylori infection should be treated irrespective of the disease phenotypes such as PUDs or MALT (mucosa-associated lymphoid tissue) lymphoma [8]. Based on the guideline, JSHR, Japanese Society of Digestive Endoscopy and Japanese Society of Gastroenterology jointly made a request to the government to approve insurance coverage for H. pylori-positive gastritis. These efforts come to fruition in February 2013, and all H. pylori infections can now be managed under coverage of public health insurance. The only condition for the reimbursement is to take an upper endoscopic examination before eradication to rule out the active PUD or neoplastic lesions requiring specific care. This policy is quite meaningful since it allows the ‘scope, test and treat’ strategy for H. pylori infection as a package and will be beneficial for patients enabling simultaneous secondary prevention (early detection of cancer and treatment) and possible primary prevention for gastric cancer by eradication. In this review, we summarize the progress in the management of H. pylori infection that has taken place since the approval of H. pylori eradication therapy in 2000 in Japan. In several points, it has notable differences from the standard management of H. pylori infection in Western guidelines.
Table 1. PPI-based triple therapy approved for H. pylori eradication as the first-line regimen
Regimen
PPI and dose
AMPC
CAM
Eradication rate, % Ref.
LAC400
lansoprazole, 30 mg b.i.d.
750 mg b.i.d.
200 mg b.i.d.
LAC800
lansoprazole, 30 mg
750 mg b.i.d.
400 mg b.i.d.
OAC400 OAC800 RAC400 RAC800 EAC800
omeprazole, 20 mg b.i.d. omeprazole, 20 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d. esomeprazole, 20 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
200 mg b.i.d. 400 mg b.i.d. 200 mg b.i.d. 400 mg b.i.d. 400 mg b.i.d.
87.5 (GU) 91.1 (DU) 89.2 (GU) 83.7 (DU) 81.1 80.0 86 89 84*
[9]
[11] [12] [13]
GU = Gastric ulcer; DU = duodenal ulcer. Eradication rates were ITT data except for EAC 800 study [13], in which it was not described whether the eradication rates were ITT or PP (per protocol) data. All the regimens are approved for a period of 7 days. * In this study, no descripiton was given whether the results were based on ITT or PP.
Indications and Guidelines Eradication therapy for H. pylori PUD was approved for public health coverage at the end of 2000. In accord with the government policy, JSHR strongly recommended eradication therapy for H. pylori-positive peptic ulcers [15]. Furthermore, the Japanese clinical guideline for gastric ulcer [16] placed eradication therapy as the first-line therapy for H. pylori-positive ulcers. In addition to this indication, a number of observational studies demonstrated that H. pylori eradication could bring about regression of H. pylori-positive MALTlymphoma patients without chromosomal abnormalities [17, 18]. JSHR, therefore, made a minor revision of the H. pylori Management in Japan
Diagnosis of gastritis by upper GI endoscopy (EGD)
Diagnosis of H. pylori infection (RUT, UBT, SAT, etc.) First-line triple therapy for 7 days (PPI + AMPC + CAM)
Failure
Cure
Second-line triple therapy for 7 days (PPI + AMPC + MNZ)
Failure
Cure
Third-line rescue therapy (arbitrary, not covered by insurance)
Fig. 2. Flow diagram of eradication program for H. pylori infection
according to the government regulation. Framed procedures and treatments are covered by health insurance. EGD = Esophagogastroduodenoscopy; RUT = rapid urease test; UBT = urea breath test; SAT = stool antigen test.
guideline [19] for the management of H. pylori in which MALT lymphoma was categorized into ‘strongly recommended for eradication’ criteria in addition to PUD. Eradication therapies were shown to exert beneficial effects on additional conditions such as metachronous gastric cancer occurrence after endoscopic treatment [5], Dig Dis 2014;32:281–289 DOI: 10.1159/000357859
283
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/13/2015 7:03:33 AM
based regimen approved through public knowledgebased application (PKBA) without clinical trial in 2011. Thus, only limited results of esomeprazole-based eradication therapy are available in Japan [13] (table 1). It should be noted that in all these regimens, the approved doses of both antibiotics were lower than those used in the Western regimens [14]. In most institutions, CAM 400 mg per day is preferred over 800 mg because of better tolerability. A second-line treatment using MNZ (250 mg, b.i.d.) instead of CAM was also approved in 2007 through PKBA in the face of declining eradication rate with the first-line regimen in the real clinical setting. This regimen (PPIAM) is only permitted when the first-line therapy has failed. The two regimens are used in the sequential manner, and the current flow of H. pylori management according to the health insurance regulation in Japan is shown in figure 2.
Table 2. Results of eradication therapy with PPI, AMPC and MNZ in Japan
Regimen
PPI
AMPC
MNZ
Duration, days
Eradication rate, %
Ref.
LAM
lansoprazole, 30 mg b.i.d. lansoprazole, 30 mg b.i.d. lansoprazole, 30 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d.
7 10 7
96.2 93.7 91.1
27 28 30
OAM
omeprazole, 20 mg b.i.d. omeprazole, 20 mg b.i.d.
500 mg t.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d.
10 7
84.5 90.9
28 30
RAM
rabeprazole, 20 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d. rabeprazole, 10 mg b.i.d.
750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d. 750 mg b.i.d.
250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d. 250 mg b.i.d.
7 7 7 7
88 82 92.4 91.4
25 26 29 30
Eradication rates are expressed as intention-to-treat-based data.
Current Status of Eradication Therapy As shown in previous sections, the first-line regimens demonstrated satisfactory eradication rates in the clinical trials [9–12]. However, a gradual decline in the eradication rate with this regimen (
