Article Text

Original article
Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study
  1. Kentaro Sugano1,
  2. Myung-Gyu Choi2,
  3. Jaw-Town Lin3,
  4. Shinya Goto4,
  5. Yasushi Okada5,
  6. Yoshikazu Kinoshita6,
  7. Hiroto Miwa7,
  8. Chern-En Chiang8,
  9. Tsutomu Chiba9,
  10. Masatsugu Hori10,
  11. Yasushi Fukushima11,
  12. Hyun-Soo Kim12,
  13. Chi-Yang Chang13,
  14. Masataka Date14,
  15. on behalf of the LAVENDER Study Group
  1. 1Department of Medicine, Jichi Medical University, Tochigi, Japan
  2. 2Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea
  3. 3School of Medicine, E-Da Hospital, Kaohsiung and Fu Jen Catholic University, Taipei, Taiwan
  4. 4Division of Cardiology, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan
  5. 5Department of Cerebrovascular Medicine and Neurology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
  6. 6Department of Gastroenterology & Hepatology, Shimane University School of Medicine, Shimane, Japan
  7. 7Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
  8. 8Department of Medical Research and Education, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan
  9. 9Division of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  10. 10Osaka Medical Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
  11. 11Department of Internal Medicine, Tokyo-Eki Center-building Clinic, Tokyo, Japan
  12. 12Division of Gastroenterology & Hepatology, Yonsei University Wonju College of Medicine, Wonju Christian Hospital, Wonju, Korea
  13. 13Division of Gastroenterology & Hepatology, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan
  14. 14Research & Development, AstraZeneca, Osaka, Japan
  1. Correspondence to Professor Kentaro Sugano, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; sugano{at}jichi.ac.jp

Abstract

Objectives To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.

Methods In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81–324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan–Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.

Results A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p<0.001). Treatment with esomeprazole was generally well tolerated.

Conclusions Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.

ClinicalTrial.gov identifier NCT01069939.

  • CLINICAL TRIALS
  • ASPIRIN
  • PROTON PUMP INHIBITION
  • GASTRIC AND DUODENAL ULCERS

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Significance of this study

What is already known on this subject?

  • Continuous low-dose acetylsalicylic acid (ASA) therapy is indicated for cardiovascular prevention and has been associated with GI intolerance, GI bleeding and peptic ulcers.

  • Proton pump inhibitors (PPIs) have been shown to be effective at reducing ulcer events in Western patients receiving low-dose ASA and at high GI risk, while there are limited clinical trial data in comparable East-Asian patients.

What are the new findings?

  • East-Asian patients on continuous low-dose ASA therapy for cardiovascular prevention experienced longer time to peptic ulcer recurrence and higher ulcer-free rates with daily esomeprazole treatment compared with placebo.

  • Esomeprazole 20 mg daily was well tolerated in the population studied.

How might it impact on clinical practice in the foreseeable future?

  • PPIs such as esomeprazole may become a widely used therapy in East-Asian patients taking continuous low-dose ASA for cardiovascular prevention who are at high GI risk, due to their ability to prevent recurrent ulcers.

Introduction

Low-dose acetylsalicylic acid (ASA, aspirin; generally defined as 75–325 mg/day) is widely recommended by clinical guidelines for prevention of cardiovascular and cerebrovascular events in at-risk patients.1 ,2 However, long-term low-dose ASA use has been associated with upper GI problems such as GI symptoms,3 ,4 peptic ulcers and GI bleeding.38 Such problems are one of the main reasons for patients to discontinue, or take deliberate breaks from, their low-dose ASA therapy.4 ,9 Low-dose ASA discontinuation is associated with a markedly increased risk of serious adverse cardiovascular events within a short timeframe.1012

Given that continuing to treat patients at cardiovascular risk with low-dose ASA is key to the long-term management of cardiovascular disease, concomitant gastroprotection with a proton pump inhibitor (PPI) is recommended for patients at increased GI risk.13 Indeed, previous studies in largely Western populations have established the therapeutic benefit of esomeprazole in this regard.14 ,15 However, few studies of PPIs have been conducted in East-Asian patients.16 ,17 These patients are known to display differences in cytochrome (CYP) P450 polymorphisms compared with Caucasian populations, as reviewed by Kurose et al,18 which may affect the metabolism of PPIs.19 The purpose of the present study, therefore, was to assess the efficacy and safety of esomeprazole for the prevention of recurrent peptic ulcers in East-Asian adult patients receiving daily low-dose ASA for cardiovascular prevention.

Methods

This was a randomised, double-blind, placebo-controlled, multicentre, parallel-group study conducted at 57 locations in three countries (Japan, Korea and Taiwan) between February 2010 and January 2012 (ClinicalTrials.gov identifier: NCT01069939). The study was conducted in accordance with the Declaration of Helsinki and its amendments, as is consistent with Good Clinical Practice guidelines. The study protocol was approved by an institutional review board at each treatment centre, in accordance with local laws, and written informed consent was obtained from all patients prior to study start.

Patients

Eligible patients were aged ≥20 years with a medical history of peptic (gastric and/or duodenal) ulcer. All participants underwent endoscopy at enrolment and were considered eligible if gastric and/or duodenal ulcer scarring was confirmed. Patients were also eligible if they did not have evidence of ulcer scarring but had clear evidence of open ulcer according to a previous endoscopy. A further inclusion criterion was the presence of a chronic thrombotic condition (myocardial infarction, cerebrovascular disease, etc) for which they were already taking low-dose ASA therapy. Female patients were eligible if they were not lactating and had provided a negative urine pregnancy test.

Patients were excluded if they had active ulcer (as evidenced by endoscopy) at enrolment; a history of GI surgery (excluding closure) or current or past evidence (within 12 weeks of randomisation) of a GI disorder (eg, Crohn's disease, inflammatory bowel disease, Zollinger–Ellison syndrome, any malabsorption syndrome, reflux oesophagitis (Los Angeles (LA) classification grade A to D) or gastric outlet obstruction; malignancy; severe liver or renal disease; severe cardiovascular or cerebrovascular disease; uncontrolled diabetes mellitus; unstable hypertension; pancreatitis; or severe pulmonary disease. Patients with scarring related to other conditions or endoscopic therapy, such as endoscopic mucosal resection or endoscopic submucosal dissection, were also excluded. Patients were restricted from using other PPIs or concomitant medications that would exacerbate GI symptoms (excluding non-steroidal anti-inflammatory drug use for ≤7 days) or interact with study medication (eg, atazanavir, digoxin and itraconazole). Patients were also excluded if they needed to continue treatment with anticoagulants after randomisation. After study commencement, the protocol was amended to restrict concomitant use of cilostazole, ketoconazole and clopidogrel.

Patients were eligible regardless of whether they were Helicobacter pylori-positive or -negative. A relevant serology test for the presence of infection (IgG antibody: E Plate ‘Eiken’ H pylori Antibody test) was completed at randomisation. CYP2C19 genotyping (homozygous extensive metaboliser (EM) genotype, heterozygous EM genotype or poor metaboliser (PM) genotype) information was collected using fluorescence correlation spectroscopy. These tests were completed by a central laboratory (SRL Inc, Tokyo, Japan).

Treatment and design

Figure 1 shows the study design. Enrolled patients were randomised 1:1 by a computer-assigned randomisation code generated by the study sponsor to receive esomeprazole 20 mg daily (esomeprazole magnesium, AstraZeneca; referred to elsewhere in this paper as ‘esomeprazole’) or matching placebo capsules taken after breakfast, for ≤72 weeks, in addition to ongoing prescribed low-dose ASA (81–324 mg/day for ≤5 of 7 days each week; taken at the same time as the study medication). Complying with the current standard practice in Asia,16 all patients received a gastroprotective agent (gefarnate 50 mg twice daily). Both physicians and patients were blinded to study treatment and all medications. To assess compliance, patients were instructed to return all unused study medications and to record their low-dose ASA use in a diary, which was reviewed at each 4-week study visit.

Figure 1

Study design. ASA: acetylsalicylic acid; E: endoscopy; R: randomisation. At each endoscopy, the following were performed: confirmation of presence/absence of gastric and/or duodenal ulcer; assessment of degree of gastric mucosal lesions; and confirmation of presence/absence and severity of reflux oesophagitis.

As defined by the protocol, the study design incorporated an interim analysis to assess the superiority of esomeprazole relative to placebo when a minimum of 18 ulcer events occurred in the overall patient population, and >250 patients had been randomised to treatment. Thereafter, a date for the data cut-off for interim analysis was decided by an independent Data Monitoring Committee, and events occurring after this time were not included in the analysis.

Study assessments

Each patient underwent planned endoscopy at 12-week intervals until study end or upon early withdrawal. Assessments included presence/absence of gastric and/or duodenal ulcer, and incidence and severity of reflux oesophagitis by the LA classification. The presence of an ulcer was defined as a mucosal defect ≥3 mm, measured using endoscopic forceps. Endoscopic findings (for ulcer scarring and recurrence) were reviewed and validated by an independent and blinded Central Evaluation Committee (CEC) consisting of two gastroenterologists (YK and HM).

In additional to endoscopic endpoints, the incidence and severity of six prespecified GI symptoms were assessed by the investigator at 12-week study visits, based on 1-week patient recall. Symptoms were evaluated on a 4-point scale, from ‘none’ to ‘severe’. Safety and tolerability were assessed at 4-week intervals, until week 72, and included incidence and severity of adverse events, laboratory data and vital signs.

Statistical analysis

Efficacy endpoints at week 48 are reported in the present manuscript. This a priori-defined interim analysis was conducted in accordance with the criteria outlined above (ie, a minimum of 18 ulcer events in the overall population and >250 patients randomised to treatment). Efficacy analyses were performed in the full analysis set (FAS), defined as all randomised patients who received at least one dose of study medication and had no active ulcer at baseline. The primary endpoint of time to recurrence of peptic ulcer was analysed using the Kaplan–Meier method, and the Greenwood formula was used to calculate 96.65% CIs for estimated ulcer-free rates, in order to adjust for multiplicity due to the interim analysis.20 The log-rank test was used for statistical comparisons.

Secondary analyses of the primary endpoint were conducted using Cox proportional-hazards model, which provided p values based on the Wald test, to determine the effects of treatment by group, gender, age, H pylori status, ASA dose, CYP2C19 genotype, smoking habit, alcohol use and use of antiplatelet drugs on the time to ulcer recurrence.

Secondary endpoints included the observed (endoscopy-confirmed) ulcer-free rate, with 95% CIs calculated by the Newcombe–Wilson method without continuity correction.21 Comparisons were made using the χ2 test. Descriptive statistics were used to summarise the following secondary endpoints: incidence and severity of reflux oesophagitis, incidence of GI symptoms and safety findings (presented for the entire 72-week treatment period). Satisfactory compliance was defined as taking 75% or more of prescribed study medication and 70% or more of prescribed low-dose ASA.

Data from a previous phase III study (NCT00441727) were used to estimate an ulcer recurrence rate of 7.4% for placebo and 1.5% for esomeprazole 20 mg daily at 6 months.14 A population size of 426 subjects was required to detect a treatment difference of 5.9% between groups, with a two-sided significance level of 2.94% and >90% power, assuming a 15% discontinuation rate.

Results

A total of 914 patients were enrolled in the study, 430 of whom were randomised to receive esomeprazole or placebo once the interim analysis criteria were applied in accordance with the study protocol (≥18 ulcer events in the overall patient population and >250 patients randomised), at week 48 (figure 2). Of the 484 patients who were not randomised, 462 patients did not have a previous history of peptic ulcer. The 22 remaining patients chose to discontinue from the study. In total, 301 patients completed the study. The most common reasons for discontinuation from the study were adverse events (n=39), ulcer recurrence (n=40) and unwillingness to continue (n=29). Of the 430 randomised patients, 51 and 78 in the esomeprazole and placebo groups, respectively, discontinued from the study. The interim FAS therefore consisted of 364 patients assigned to esomeprazole 20 mg (n=182) or placebo (n=182).

Figure 2

Patient disposition.

Randomised subjects (FAS efficacy population) were well matched at baseline (table 1). Most patients were Japanese and men; the mean age was 67.1 years. A large proportion of patients were receiving a daily ASA dose of 100 mg, and the majority had received low-dose ASA for >4 weeks prior to the study. Overall, 44.8% (n=163) of patients were H pylori-positive and H pylori data were missing in 3.3% (n=12) (table 1). Patients’ CYP2C19 metaboliser status is described in table 1. Approximately 10% of patients (n=42) within the FAS efficacy population used additional antiplatelet drugs during the study. Five patients (1.4%) received concomitant clopidogrel (esomeprazole, n=1; placebo, n=4); such patients were enrolled into the study before the protocol amendment described in the Methods section was instituted. A further 15 patients (4.1%) received ticlopidine in addition to low-dose ASA (esomeprazole, n=4; placebo, n=11).

Table 1

Demographic and baseline characteristics (48-week full analysis set)

Overall, the proportion of patients who were deemed to be compliant with study medication (defined as taking ≥75% of prescribed medication) was 92.3% (n=168) for esomeprazole 20 mg daily, 92.9% (n=169) for placebo and 90.7% (n=330) for gefarnate (administered in both groups). Some 94.2% of patients (n=343) were compliant with low-dose ASA therapy (defined as taking ≥70% of prescribed doses).

Primary endpoint: time to ulcer recurrence

Two esomeprazole-treated patients and 22 patients in the placebo group developed an ulcer by week 48, nearly a half of which were gastric-only in nature (n=20 ulcers). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole 20 mg daily and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001 (log-rank test)) (figure 3). Esomeprazole treatment (HR 0.07; 96.65% CI 0.01 to 0.37; p<0.001 (Wald test)) and female gender (HR 0.33; 96.65% CI 0.11 to 0.96; p=0.026 (Wald test)) were the only factors that significantly reduced the time to ulcer recurrence in the Cox proportional-hazard model.

Figure 3

Estimated peptic ulcer-free rate, by Kaplan–Meier method.

A total of 349 patients were included in the FAS investigation conducted by the blinded CEC (esomeprazole, n=173; placebo, n=176). Most patients excluded from this FAS were removed because there was no ulcer scar at baseline, as judged by the CEC (n=15/364). A total of 22 patients in the CEC FAS developed a peptic ulcer by week 48. Similarly to the primary FAS, statistically significant differences in the time to ulcer recurrence were observed between esomeprazole and placebo groups (HR 0.05; 96.65% CI 0.01 to 0.045; p<0.001 (log-rank test)).

Secondary endpoints

In the FAS, estimated ulcer-free rates at week 12 were 99.3% and 89.0% for the esomeprazole and placebo groups, respectively; these high estimated ulcer-free rates were maintained for esomeprazole through week 48 (98.3% vs 81.2% for placebo). The analysis by blinded CEC yielded similar estimated ulcer-free rates (99.0% vs 82.8% for placebo). Overall, the estimated ulcer-free rate was high for all subgroups analysed in the esomeprazole group (table 2). Factors associated with a decreased ulcer-free rate in the placebo group included low-dose ASA intake for <2 weeks prior to enrolment, age ≤64 years, H pylori-positive status and CYP2C19 PM genotype. A statistically significant difference in the observed ulcer-free rate was noted between esomeprazole and placebo (p<0.001 (χ2 test)) from week 12 (99.5% (181/182) vs 91.2% (166/182)) to week 48 (98.9% (180/182) vs 87.9% (160/182)).

Table 2

Estimated ulcer-free rate by subgroup at week 48, by Kaplan–Meier method (full analysis set)

Only one case of reflux oesophagitis (LA grade A) was reported in the esomeprazole group, whereas 18 cases were reported in the placebo group; of these, 11 were LA grade A, five were grade B and two were grade C.

At baseline, most patients in both treatment groups did not report GI symptoms (see online supplementary table S1). Slightly more patients in the placebo group with no baseline GI symptoms experienced mild-to-severe epigastric pain, heartburn, anorexia, nausea and vomiting and stomach discomfort at study end compared with esomeprazole-treated patients. Furthermore, while more patients in the placebo group experienced ulcers compared with esomeprazole recipients, few moderate-to-severe GI symptoms were observed. More esomeprazole-treated patients than placebo recipients also experienced abdominal fullness.

Safety findings

Safety findings are presented for the whole 72-week treatment period; overall, the mean treatment duration was 293 days for esomeprazole and 209 days for placebo.

Esomeprazole was well tolerated; the distribution of adverse events and serious adverse events was generally comparable with placebo (table 3). Numerically more patients in the placebo than esomeprazole group discontinued from the study due to adverse events (22 with placebo vs 17 with esomeprazole). Similar trends were observed for the severe adverse events (10 vs 7, respectively). Myocardial infarction (a serious adverse event) occurred in two placebo recipients and in no patients treated with esomeprazole; furthermore, no deaths were reported overall. Numerically more drug-related adverse events occurred in the placebo group than among esomeprazole-treated patients, of which the majority were GI in nature and included constipation, gastritis and duodenitis. There were no fractures, cases of pneumonia or clinically significant changes in vital signs and laboratory assessments in the esomeprazole treatment group. One patient in the placebo group (0.5%) experienced a hip fracture and one patient (0.5%) was diagnosed with pneumonia; no clinically relevant changes in vital signs or laboratory assessments were seen in the placebo group.

Table 3

Summary of adverse events (AEs) (safety analysis set*)

Discussion

In this study, esomeprazole 20 mg daily over 48 weeks prevented the recurrence of peptic ulcers in East-Asian patients receiving continuous low-dose ASA therapy for cardiovascular protection. Statistically significant differences in time to ulcer recurrence were observed in the primary (interim) analysis, as well as in the blinded CEC analysis. Estimated and observed ulcer-free rates were consistently higher with esomeprazole than placebo through week 48, as were estimated ulcer-free rates in predefined subgroup analyses. For placebo, female gender, low-dose ASA intake for <2 weeks for the prestudy treatment condition, age ≤64 years, CYP2C19 PM genotype and H pylori-positive status were associated with the lowest estimated ulcer-free rates. The fact that H pylori-positive patients had lower ulcer-free rates is in accordance with certain studies showing a synergistic interaction between the infection and low-dose ASA in terms of increased GI risk,22 although this relationship remains controversial.23 Indeed, recent evidence points towards a biphasic effect of H pylori infection on low-dose ASA-associated gastropathy that depends on the level of gastric acid secretion.24 Higher rates of ulcer recurrence among younger patients (≤64 years) was an unexpected finding, as older age (>70 years) is generally regarded as a GI risk factor with low-dose ASA therapy.25 Similarly, higher rates of ulcer recurrence among female placebo recipients was unexpected, as gender is not generally considered to be a risk factor for peptic ulcer, and animal studies suggest that female sex hormones may protect against ASA-associated mucosal injury.26 However, the present study recruited a large enough number of elderly patients and therefore any potential protective effects of female sex hormones would have been diminished in view of menopause-related changes. The estimated ulcer-free rate was lower in placebo recipients who had been receiving low-dose ASA for <2 weeks prior to study start. This was unexpected as longer duration of low-dose ASA use is associated with increased risk of ulcer development.27 This result may be attributable to the variability when we applied Kaplan–Meier method to estimate ulcer-free rates in a small number of patients. Indeed, only three patients (two esomeprazole and one placebo recipient) in this group (low-dose ASA for <2 weeks) underwent endoscopy at the maximum duration. One placebo recipient had ulcer recurrence at that time point, which led to a reduced occurrence-free rate (0%). With respect to CYP2C19 genotype, it is unclear why PM placebo recipients showed lower ulcer-free rates (72.9%) than homozygous EM (83.3%) and heterozygous EM (83.3%) placebo recipients, when one would expect little difference between the three groups. However, the small population of placebo PM patients (n=35 vs 66 and 77 homozygous and heterozygous EM patients, respectively) may have affected the validity of this result. This difference aside, esomeprazole protected against ulcer recurrence irrespective of CYP2C19 genotype.

These findings add to previous experience of esomeprazole efficacy in a similar population of Western patients receiving low-dose ASA for cardiovascular protection.14 ,15 In the 26-week OBERON study, ulcer rates of 1.1% and 1.5% were observed with esomeprazole 20 and 40 mg, respectively, compared with 7.4% for placebo (p<0.0001 vs placebo for both).14 Similarly, in the ASTERIX study, 26 weeks of esomeprazole 20 mg daily resulted in significantly fewer peptic ulcers compared with placebo (1.6% vs 5.4%; p=0.0007).15 Therefore, the present study is notable for a high ulcer recurrence rate among placebo recipients; possible explanations include the differences in patients’ baseline characteristics and higher H pylori infection rates relative to Western populations. Indeed, the present study enrolled only patients with a history of peptic ulcer, whereas OBERON14 and ASTERIX15 included patients with and without a history of such events. As outlined above, patients with active H pylori infection and continuous use of low-dose ASA may have an increased upper GI risk.22 In the present East-Asian study, 45% of randomised patients were H pylori-positive, compared with 21% and 23% of patients, respectively, in the OBERON14 and ASTERIX15 studies. Nevertheless, esomeprazole protected against ulcer recurrence irrespective of H pylori status in this population of at-risk East-Asian patients receiving low-dose ASA.

Two recent randomised studies investigated the gastroprotective effects of lansoprazole16 and rabeprazole17 in East-Asian patients receiving continuous low-dose ASA therapy. Lansoprazole 15 mg daily was associated with a peptic ulcer rate of 3.7% over 12 months compared with 31.7% for gefarnate 50 mg twice daily,16 while rabeprazole 5 and 10 mg daily was associated with an ulcer rate of 5.5% at 12 weeks versus 26.7% for gefarnate.17 Considering this in tandem with the results of the present study (where patients in the placebo group also received gefarnate for mucosal protection as we considered it unethical to withhold this treatment in such at-risk patients), it is reasonable to assert that gefarnate alone is not sufficient to prevent ulcer recurrence in at-risk East-Asian patients receiving continuous low-dose ASA therapy. Therefore, while it could be argued that the use of gefarnate might have confounded our results, its use in this study is not likely to significantly impinge upon the potential effects of esomeprazole. Additionally, its use in clinical trials is standard in Asia;16 ,17 thus, our study design is a closer representation of a clinical trial in our target population.

With regard to the gastroprotective effects of esomeprazole, fewer esomeprazole-treated patients than placebo recipients shifted from no GI symptoms at baseline to experiencing mild-to-severe GI symptoms. This trend was observed for five of six GI symptoms evaluated. When looking at patients whose GI symptoms worsened regardless of baseline symptom status, the differences between treatment groups were most prominent for heartburn (three esomeprazole vs 12 placebo recipients) and nausea and vomiting (0 vs 13, respectively). In the ASTERIX study, esomeprazole demonstrated similar gastroprotective effects, preventing more epigastric burning and heartburn than placebo (p<0.05), as well as resolving epigastric pain and heartburn in patients who reported the same symptoms at baseline (p=0.047 and p=0.0131 vs placebo, respectively).15 Notably, although ulcer recurrence was high among placebo recipients in the present study, few experienced moderate or severe GI symptoms. This implies that low-dose ASA-associated ulcers are typically ‘silent’, which underscores the importance of objective evaluation of ulcer recurrence (as was used in this study), and that gastroprotective therapies may increase the likelihood that patients will remain adherent to continuous low-dose ASA therapy—an important aspect of cardiovascular risk management.

Esomeprazole was well tolerated, and more patients discontinued placebo than esomeprazole. Most adverse events were GI disorders. Rates of diarrhoea were very low in both groups (0.9%). This is in contrast to findings of significantly higher rates of diarrhoea with lansoprazole compared with gefarnate in a similar study (8.4% vs 0.9%, p<0.001).16

It is important to consider concerns related to an increased risk of adverse cardiovascular outcomes in patients taking low-dose ASA and PPIs concomitantly.28 However, in the present study, there were no reports of myocardial infarction in esomeprazole-treated patients (although two events were reported in the placebo group). This mirrors the findings of no myocardial infarctions in esomeprazole recipients in the ASTERIX study, while in OBERON, only one case of myocardial infarction was reported in a patient taking esomeprazole 40 mg. To date, no pharmacokinetic or pharmacodynamic interactions have been observed between low-dose ASA and esomeprazole.29 ,30 Concern has also been raised recently about the possibility of an increased risk of fracture31 and pneumonia32 with long-term PPI treatment; however, no cases of fracture or pneumonia were reported here with long-term esomeprazole therapy.

Information on ulcer-related complications was not collected, and represents one weakness of this study. Other possible drawbacks include the potential for inter-observer variation with regard to the assessment of GI symptoms in general, due to the multi-site and multi-country nature of this trial. This potential for inter-observer variation is inherent to all similar trials using subjective measures and was unavoidable. Nonetheless, in order to reduce the potential for confounding, investigators were provided with strict guidelines, criteria and training to ensure a consistent approach to the assessment of all variables. It could be argued that inclusion of both H pylori-positive and -negative patients may confound these results. However, there is conflicting evidence as to whether H pylori eradication significantly reduces the rate of ulcer recurrence,25 ,33 with some studies showing no significant difference between patients with an ulcer history who were H pylori-negative, H pylori-positive or who had undergone H pylori eradication.33 As was shown in a similar trial,16 we could not find significant difference in terms of ulcer relapse according to the H pylori status.

East-Asian populations frequently display differences in CYP450 polymorphisms that are known to impact the efficacy and safety of a given drug.18 ,19 As no large-scale trials of esomeprazole plus low-dose ASA in East-Asian patients at high cardiovascular risk have been conducted, this study represents the first findings that this regimen is indeed efficacious and well tolerated in this specific population of patients. This outcome is consistent with previous studies which reported that PPI therapy is more effective in Asia.34

Conclusions

Esomeprazole 20 mg daily was efficacious and well tolerated for the prevention of ulcer recurrence in a population of East-Asian patients with a history of peptic ulcers who required long-term low-dose ASA for cardiovascular protection. The randomised, controlled design represents a strength of this study, and confirms previous findings of the efficacy of esomeprazole in Western patient populations.

Acknowledgments

Medical writing support was provided by Robert Schupp and Steve Winter, from inScience Communications, Springer Healthcare and funded by AstraZeneca, Osaka, Japan. The data analysis in this paper was conducted by the statistician at AstraZeneca, and programming/analysis conducted by CAC EXICARE corporation in Japan, a clinical research organisation independent from AstraZeneca.

References

Supplementary materials

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Footnotes

  • *Low-dose Aspirin-related ulcer recurrence preVENtion unDER esomeprazole 20 mg treatment.

  • Collaborators The authors are indebted to the LAVENDER Study Group for their contribution to this study. In Japan: Medical Corporation Hojin kai Yamauchi Internal Medicine Clinic; National Hospital Organization Sendai Medical Center; Ohara General Hospital; Social Insurance Nihonmatsu Hospital; Social Welfare Organization Saiseikai Imperial Gift Foundation Fukushima General Hospital; Southern Tohoku Research Institute for Neuroscience, Southern Tohoku Fukushima Hospital and Medical Clinic; National Hospital Organization Mito Medical Center; Hanyu General Hospital; Yotsukaidou Tokushukai Hospital; Kanto Medical Center NTT EC; Kitasato University Kitasato Institute Hospital; National Center for Global Health and Medicine; Tokyo Eki Center Building Clinic; Medical Corporation Kokan kai Kokan Clinic; Yokohama Asahi Chuo General Hospital; Medical Corporation Houju Memorial Hospital; Medical Corporation Aikoukai Katou Hospital; Fukui ken Saiseikai Hospital; Shizuoka Tokushukai Hospital; Uji Tokushukai Hospital; Yao Tokushukai General Hospital; Matsubara Tokushukai Hospital; Kishiwada Tokushukai Hospital; Osaka Seamen's Insurance Hospital; Itami City Hospital; Medical Corporation Rougenkai Ookuma Hospital; Kobe Tokushukai Hospital; Nishinomiya Kyoritsu Neurosurgical Hospital; National Hospital Organization Fukuyama Medical Center; National Hospital Organization Kure Medical Center and Chugoku Cancer Center; National Hospital Organization Kanmon Medical Center; Fukuoka Wajiro Hospital; Keio University Hospital; Jichi Medical University Hospital; Miyanomori Memorial Hospital; Shin Yukuhashi Hospital; Shin Komonji Hospital; Fukuoka Shin Mizumaki Hospital; Medical Corporation Tokushukai Nozaki Tokushukai Hospital; and Nanbu Tokushukai Hospital. In Taiwan: Taipei Veterans General Hospital; National Taiwan University Hospital; Chang-Gung Memorial Hospital-Linkou; Shin Kong Memorial Hospital; National Cheng Kung University Hospital; Kaohsiung Medical University Hospital; Chang-Gung Memorial Hospital-Kaohsiung; E-Da Hospital; and Chung Shan Medical University Hospital. In Korea: Seoul St. Mary's Hospital; Korea University Anam Hospital; Seoul National University Bundang Hospital; Wonju Christian Hospital; Inje University Pusan Paik Hospital; Soonchunhyang University Hospital; and Gangneung Asan Hospital.

  • Contributors KS: Planning and steering the study, international coordination of the study, patient recruitment, data analysis, and writing the manuscript; M-GC and J-TL: Planning and international coordination of the study, patient recruitment, data analysis, and writing the manuscript; SG and YO: Planning and international coordination of the study, data analysis, and writing the manuscript; YK and HM: Central Evaluation of EGD, data analysis and writing the manuscript; TC and MH: Independent data monitoring, data analysis and writing the manuscript; C-EC: National coordination of the study in Taiwan, patient recruitment, data analysis and writing the manuscript; YF, H-SK and C-YC: Patient recruitment, data analysis and writing the manuscript; MD: Planning, data analysis and writing the manuscript.

  • Funding This study was supported by AstraZeneca, Osaka, Japan.

  • Competing interests KS has received financial support for research from Astellas, AstraZeneca, Daiichi Sankyo, Eisai, Otsuka and Takeda, and has served as a paid consultant to AstraZeneca and Takeda; he has also received honoraria from Takeda. M-GC and J-TL have received financial support for research from AstraZeneca. SG has received financial support for research from Boehringer Ingelheim, Eisai, Otsuka and Sanofi, and has been paid lecture fees by AstraZeneca, Eisai, Otsuka and Sanofi; he has also served as a paid consultant to Bayer, MSD and Pfizer, and has received honoraria from Bayer and Bristol-Myers Squibb. YK has received financial support for research and was the recipient of honoraria from AstraZeneca and Daiichi Sankyo. HM has received financial support for research from AstraZeneca, Chugai, Dainippon Sumitomo, Eisai, Takeda and Yakult, has served as a paid consultant to AstraZeneca, Daiichi Sankyo and Eisai, and has held directorship at AstraZeneca and Takeda. TC has received financial support for research from Astellas, AstraZeneca, Eisai and Takeda, and has served as a paid consultant to and has been the recipient of honoraria from Takeda. C-EC, H-SK, C-YC, YO, MH and YF have no competing interests to declare. MD is a current employee of AstraZeneca.

  • Patient consent Obtained.

  • Ethics approval This is a multinational and multicentre study. Therefore, clinical trial protocol was approved in each institution before recruitment of subjects.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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