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Active and Non-Active Comparators Yield Different Estimates of the Association Between Proton Pump Inhibitor Use and Recorded Mortality During Immune Checkpoint Inhibitor Therapy for Advanced Non-Small Cell Lung Cancer.

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Τίτλος: Active and Non-Active Comparators Yield Different Estimates of the Association Between Proton Pump Inhibitor Use and Recorded Mortality During Immune Checkpoint Inhibitor Therapy for Advanced Non-Small Cell Lung Cancer.
Συγγραφείς: Ihara Y; Clinical Research Promotion Unit, Clinical Therapeutic Trial Center, Ehime University Hospital, Toon, Ehime, Japan.; Center for Data Science, Ehime University, Matsuyama, Ehime, Japan.; Integrated Medical and Agricultural School of Public Health, Ehime University, Toon, Ehime, Japan., Okada N; Pharmacy Department, Yamaguchi University Hospital, Ube, Yamaguchi, Japan., Mizutani M; Department of Respiratory Medicine, Yodogawa Christian Hospital, Osaka, Japan., Nakamura Y; Department of Cardiology, Pulmonology, Hypertension & Nephrology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan., Shimomura Y; Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan., Yamamoto S; Department of Respiratory Medicine, Yodogawa Christian Hospital, Osaka, Japan.; Department of Clinical Oncology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
Πηγή: Pharmacoepidemiology and drug safety [Pharmacoepidemiol Drug Saf] 2026 Sep; Vol. 35 (9), pp. e70478.
Τύπος έκδοσης: Journal Article; Comparative Study
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Wiley Country of Publication: England NLM ID: 9208369 Publication Model: Print Cited Medium: Internet ISSN: 1099-1557 (Electronic) Linking ISSN: 10538569 NLM ISO Abbreviation: Pharmacoepidemiol Drug Saf Subsets: MEDLINE
Imprint Name(s): Original Publication: Chichester, West Sussex : Wiley, 1992-
Ιατρικοί όροι (MeSH): Proton Pump Inhibitors*/adverse effects , Proton Pump Inhibitors*/administration & dosage , Proton Pump Inhibitors*/therapeutic use , Carcinoma, Non-Small-Cell Lung*/drug therapy , Carcinoma, Non-Small-Cell Lung*/mortality , Carcinoma, Non-Small-Cell Lung*/pathology , Lung Neoplasms*/drug therapy , Lung Neoplasms*/mortality , Lung Neoplasms*/pathology , Immune Checkpoint Inhibitors*/therapeutic use , Immune Checkpoint Inhibitors*/administration & dosage, Japan/epidemiology ; Histamine H2 Antagonists/administration & dosage ; Histamine H2 Antagonists/adverse effects ; Histamine H2 Antagonists/therapeutic use ; Databases, Factual/statistics & numerical data ; Humans ; Female ; Retrospective Studies ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; Proportional Hazards Models ; Propensity Score ; Cohort Studies
Περίληψη: Purpose: Proton pump inhibitor (PPI) use has been associated with poorer outcomes in patients receiving immune checkpoint inhibitors (ICIs), but most previous studies have compared PPI users with non-users, which may differ in their underlying need for acid-suppressive therapy. We evaluated the association between PPI use and mortality using histamine-2 receptor antagonist (H2RA) users as an active comparator among patients with advanced non-small cell lung cancer (NSCLC) receiving ICIs.
Methods: We conducted a retrospective cohort study using a Japanese administrative claims database. Patients with advanced NSCLC who initiated first-line ICI-based therapy and received either a PPI or an H2RA within 30 days before or on the day of ICI initiation were included. The index date was defined as the initiation date of the first-line ICI-based regimen. The primary outcome was all-cause mortality within 3 years. Propensity score overlap weighting was used to balance baseline characteristics, and weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Among 6360 eligible patients, 5409 received conventional PPIs and 951 received H2RAs. After overlap weighting, mortality did not clearly differ between PPI and H2RA users (HR, 1.06; 95% CI, 0.93-1.20). In contrast, PPI users had higher mortality than patients receiving neither PPIs nor H2RAs (HR, 1.13; 95% CI, 1.05-1.20).
Conclusion: PPI use was not clearly associated with higher mortality when H2RA users were used as an active comparator, whereas a higher mortality estimate was observed when PPI users were compared with patients receiving neither PPI nor H2RA therapy. These findings highlight the importance of comparator selection in observational studies evaluating PPI use during ICI therapy.
(© 2026 John Wiley & Sons Ltd.)
References: N Engl J Med. 2018 Jun 14;378(24):2288-2301. (PMID: 29863955)
Nat Rev Gastroenterol Hepatol. 2017 Dec;14(12):697-710. (PMID: 28930292)
Md State Med J. 1965 Feb;14:61-5. (PMID: 14258950)
Ann Oncol. 2020 Apr;31(4):525-531. (PMID: 32115349)
Pharmacoepidemiol Drug Saf. 2022 Mar;31(3):261-269. (PMID: 35019190)
Gut. 2016 May;65(5):740-8. (PMID: 26657899)
Science. 2018 Jan 5;359(6371):104-108. (PMID: 29302014)
J Immunother Cancer. 2020 Nov;8(2):. (PMID: 33154150)
Pharmacoepidemiol Drug Saf. 2022 Jun;31(6):680-688. (PMID: 35324035)
Pharmacoepidemiol Drug Saf. 2026 Jul;35(7):e70428. (PMID: 42381293)
J Clin Oncol. 2021 Jul 20;39(21):2339-2349. (PMID: 33872070)
J Clin Epidemiol. 1994 Nov;47(11):1245-51. (PMID: 7722560)
Stat Med. 2009 Nov 10;28(25):3083-107. (PMID: 19757444)
Nat Commun. 2020 Jan 17;11(1):362. (PMID: 31953381)
Pharmacoepidemiol Drug Saf. 2024 Dec;33(12):e70048. (PMID: 39586646)
J Immunother Cancer. 2021 Apr;9(4):. (PMID: 33827906)
Gut. 2024 Jun 6;73(7):1087-1097. (PMID: 38050061)
Cancers (Basel). 2022 Mar 09;14(6):. (PMID: 35326555)
Drugs Real World Outcomes. 2022 Jun;9(2):175-187. (PMID: 35304702)
CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338)
Japan Med Assoc J. 2012 Jul;55(4):279-91. (PMID: 25237234)
Front Immunol. 2023 Jan 26;14:1070076. (PMID: 36776847)
Biometrics. 2000 Sep;56(3):779-88. (PMID: 10985216)
Gastroenterology. 2022 Apr;162(4):1334-1342. (PMID: 35183361)
Science. 2018 Jan 5;359(6371):97-103. (PMID: 29097493)
JAMA Netw Open. 2023 Jul 3;6(7):e2322915. (PMID: 37432682)
Gastroenterology. 2017 Jul;153(1):35-48. (PMID: 28528705)
JAMA. 2020 Jun 16;323(23):2417-2418. (PMID: 32369102)
Am J Epidemiol. 2003 Nov 1;158(9):915-20. (PMID: 14585769)
N Engl J Med. 2019 Nov 21;381(21):2020-2031. (PMID: 31562796)
N Engl J Med. 2018 May 31;378(22):2078-2092. (PMID: 29658856)
Br J Cancer. 2022 Jan;126(1):42-47. (PMID: 34711947)
Science. 2018 Jan 5;359(6371):91-97. (PMID: 29097494)
Contributed Indexing: Keywords: histamine‐2 receptor antagonist; immune checkpoint inhibitor; mortality; non‐small cell lung cancer; overlap weighting; pharmacoepidemiology; proton pump inhibitor
Local Abstract: [plain-language-summary] Proton pump inhibitors and histamine‐2 receptor antagonists are both used to reduce stomach acid. Proton pump inhibitors are commonly prescribed to patients with cancer, but they may alter the gut microbiome, which could influence the effectiveness of immune checkpoint inhibitors used to treat advanced non‐small cell lung cancer. Many previous studies compared proton pump inhibitor users with patients who did not use proton pump inhibitors. However, the choice of comparison group may affect the estimated association because patients who receive acid‐suppressive therapy may differ from non‐users in their underlying conditions, gastrointestinal symptoms, medication use, and clinical status. To address this issue, we compared proton pump inhibitor users with histamine‐2 receptor antagonist users as an active comparator, because both groups received acid‐suppressive therapy for overlapping indications. Using a large Japanese real‐world database, we found no clear difference in recorded mortality between proton pump inhibitor and histamine‐2 receptor antagonist users receiving immune checkpoint inhibitor–based therapy. In contrast, proton pump inhibitor use was associated with higher recorded mortality when compared with patients receiving neither proton pump inhibitors nor histamine‐2 receptor antagonists. These findings highlight the importance of selecting an appropriate comparison group when evaluating the association between proton pump inhibitor use and outcomes during immune checkpoint inhibitor therapy.
Substance Nomenclature: 0 (Proton Pump Inhibitors)
0 (Immune Checkpoint Inhibitors)
0 (Histamine H2 Antagonists)
Entry Date(s): Date Created: 20260914 Date Completed: 20260914 Latest Revision: 20260917
Update Code: 20260917
PubMed Central ID: PMC13574716
DOI: 10.1002/pds.70478
PMID: 42736173
Βάση Δεδομένων: MEDLINE
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  Data: Active and Non-Active Comparators Yield Different Estimates of the Association Between Proton Pump Inhibitor Use and Recorded Mortality During Immune Checkpoint Inhibitor Therapy for Advanced Non-Small Cell Lung Cancer.
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  Data: <searchLink fieldCode="AU" term="%22Ihara+Y%22">Ihara Y</searchLink>; Clinical Research Promotion Unit, Clinical Therapeutic Trial Center, Ehime University Hospital, Toon, Ehime, Japan.; Center for Data Science, Ehime University, Matsuyama, Ehime, Japan.; Integrated Medical and Agricultural School of Public Health, Ehime University, Toon, Ehime, Japan.<br /><searchLink fieldCode="AU" term="%22Okada+N%22">Okada N</searchLink>; Pharmacy Department, Yamaguchi University Hospital, Ube, Yamaguchi, Japan.<br /><searchLink fieldCode="AU" term="%22Mizutani+M%22">Mizutani M</searchLink>; Department of Respiratory Medicine, Yodogawa Christian Hospital, Osaka, Japan.<br /><searchLink fieldCode="AU" term="%22Nakamura+Y%22">Nakamura Y</searchLink>; Department of Cardiology, Pulmonology, Hypertension & Nephrology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.<br /><searchLink fieldCode="AU" term="%22Shimomura+Y%22">Shimomura Y</searchLink>; Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan.<br /><searchLink fieldCode="AU" term="%22Yamamoto+S%22">Yamamoto S</searchLink>; Department of Respiratory Medicine, Yodogawa Christian Hospital, Osaka, Japan.; Department of Clinical Oncology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Wiley%22">Wiley </searchLink><i>Country of Publication: </i>England <i>NLM ID: </i>9208369 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1099-1557 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2210538569%22">10538569 </searchLink><i>NLM ISO Abbreviation: </i>Pharmacoepidemiol Drug Saf <i>Subsets: </i>MEDLINE
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Purpose: Proton pump inhibitor (PPI) use has been associated with poorer outcomes in patients receiving immune checkpoint inhibitors (ICIs), but most previous studies have compared PPI users with non-users, which may differ in their underlying need for acid-suppressive therapy. We evaluated the association between PPI use and mortality using histamine-2 receptor antagonist (H2RA) users as an active comparator among patients with advanced non-small cell lung cancer (NSCLC) receiving ICIs.<br />Methods: We conducted a retrospective cohort study using a Japanese administrative claims database. Patients with advanced NSCLC who initiated first-line ICI-based therapy and received either a PPI or an H2RA within 30 days before or on the day of ICI initiation were included. The index date was defined as the initiation date of the first-line ICI-based regimen. The primary outcome was all-cause mortality within 3 years. Propensity score overlap weighting was used to balance baseline characteristics, and weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).<br />Results: Among 6360 eligible patients, 5409 received conventional PPIs and 951 received H2RAs. After overlap weighting, mortality did not clearly differ between PPI and H2RA users (HR, 1.06; 95% CI, 0.93-1.20). In contrast, PPI users had higher mortality than patients receiving neither PPIs nor H2RAs (HR, 1.13; 95% CI, 1.05-1.20).<br />Conclusion: PPI use was not clearly associated with higher mortality when H2RA users were used as an active comparator, whereas a higher mortality estimate was observed when PPI users were compared with patients receiving neither PPI nor H2RA therapy. These findings highlight the importance of comparator selection in observational studies evaluating PPI use during ICI therapy.<br /> (© 2026 John Wiley & Sons Ltd.)
– Name: Ref
  Label: References
  Group: RefInfo
  Data: N Engl J Med. 2018 Jun 14;378(24):2288-2301. (PMID: <searchLink fieldCode="PM" term="%2229863955%22">29863955)</searchLink><br />Nat Rev Gastroenterol Hepatol. 2017 Dec;14(12):697-710. (PMID: <searchLink fieldCode="PM" term="%2228930292%22">28930292)</searchLink><br />Md State Med J. 1965 Feb;14:61-5. (PMID: <searchLink fieldCode="PM" term="%2214258950%22">14258950)</searchLink><br />Ann Oncol. 2020 Apr;31(4):525-531. (PMID: <searchLink fieldCode="PM" term="%2232115349%22">32115349)</searchLink><br />Pharmacoepidemiol Drug Saf. 2022 Mar;31(3):261-269. (PMID: <searchLink fieldCode="PM" term="%2235019190%22">35019190)</searchLink><br />Gut. 2016 May;65(5):740-8. (PMID: <searchLink fieldCode="PM" term="%2226657899%22">26657899)</searchLink><br />Science. 2018 Jan 5;359(6371):104-108. (PMID: <searchLink fieldCode="PM" term="%2229302014%22">29302014)</searchLink><br />J Immunother Cancer. 2020 Nov;8(2):. (PMID: <searchLink fieldCode="PM" term="%2233154150%22">33154150)</searchLink><br />Pharmacoepidemiol Drug Saf. 2022 Jun;31(6):680-688. (PMID: <searchLink fieldCode="PM" term="%2235324035%22">35324035)</searchLink><br />Pharmacoepidemiol Drug Saf. 2026 Jul;35(7):e70428. (PMID: <searchLink fieldCode="PM" term="%2242381293%22">42381293)</searchLink><br />J Clin Oncol. 2021 Jul 20;39(21):2339-2349. (PMID: <searchLink fieldCode="PM" term="%2233872070%22">33872070)</searchLink><br />J Clin Epidemiol. 1994 Nov;47(11):1245-51. (PMID: <searchLink fieldCode="PM" term="%227722560%22">7722560)</searchLink><br />Stat Med. 2009 Nov 10;28(25):3083-107. (PMID: <searchLink fieldCode="PM" term="%2219757444%22">19757444)</searchLink><br />Nat Commun. 2020 Jan 17;11(1):362. (PMID: <searchLink fieldCode="PM" term="%2231953381%22">31953381)</searchLink><br />Pharmacoepidemiol Drug Saf. 2024 Dec;33(12):e70048. (PMID: <searchLink fieldCode="PM" term="%2239586646%22">39586646)</searchLink><br />J Immunother Cancer. 2021 Apr;9(4):. (PMID: <searchLink fieldCode="PM" term="%2233827906%22">33827906)</searchLink><br />Gut. 2024 Jun 6;73(7):1087-1097. (PMID: <searchLink fieldCode="PM" term="%2238050061%22">38050061)</searchLink><br />Cancers (Basel). 2022 Mar 09;14(6):. (PMID: <searchLink fieldCode="PM" term="%2235326555%22">35326555)</searchLink><br />Drugs Real World Outcomes. 2022 Jun;9(2):175-187. (PMID: <searchLink fieldCode="PM" term="%2235304702%22">35304702)</searchLink><br />CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: <searchLink fieldCode="PM" term="%2233538338%22">33538338)</searchLink><br />Japan Med Assoc J. 2012 Jul;55(4):279-91. (PMID: <searchLink fieldCode="PM" term="%2225237234%22">25237234)</searchLink><br />Front Immunol. 2023 Jan 26;14:1070076. (PMID: <searchLink fieldCode="PM" term="%2236776847%22">36776847)</searchLink><br />Biometrics. 2000 Sep;56(3):779-88. (PMID: <searchLink fieldCode="PM" term="%2210985216%22">10985216)</searchLink><br />Gastroenterology. 2022 Apr;162(4):1334-1342. (PMID: <searchLink fieldCode="PM" term="%2235183361%22">35183361)</searchLink><br />Science. 2018 Jan 5;359(6371):97-103. (PMID: <searchLink fieldCode="PM" term="%2229097493%22">29097493)</searchLink><br />JAMA Netw Open. 2023 Jul 3;6(7):e2322915. (PMID: <searchLink fieldCode="PM" term="%2237432682%22">37432682)</searchLink><br />Gastroenterology. 2017 Jul;153(1):35-48. (PMID: <searchLink fieldCode="PM" term="%2228528705%22">28528705)</searchLink><br />JAMA. 2020 Jun 16;323(23):2417-2418. (PMID: <searchLink fieldCode="PM" term="%2232369102%22">32369102)</searchLink><br />Am J Epidemiol. 2003 Nov 1;158(9):915-20. (PMID: <searchLink fieldCode="PM" term="%2214585769%22">14585769)</searchLink><br />N Engl J Med. 2019 Nov 21;381(21):2020-2031. (PMID: <searchLink fieldCode="PM" term="%2231562796%22">31562796)</searchLink><br />N Engl J Med. 2018 May 31;378(22):2078-2092. (PMID: <searchLink fieldCode="PM" term="%2229658856%22">29658856)</searchLink><br />Br J Cancer. 2022 Jan;126(1):42-47. (PMID: <searchLink fieldCode="PM" term="%2234711947%22">34711947)</searchLink><br />Science. 2018 Jan 5;359(6371):91-97. (PMID: <searchLink fieldCode="PM" term="%2229097494%22">29097494)</searchLink>
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  Data: <i>Keywords: </i>histamine‐2 receptor antagonist; immune checkpoint inhibitor; mortality; non‐small cell lung cancer; overlap weighting; pharmacoepidemiology; proton pump inhibitor<br /><i>Local Abstract: </i>[plain-language-summary] Proton pump inhibitors and histamine‐2 receptor antagonists are both used to reduce stomach acid. Proton pump inhibitors are commonly prescribed to patients with cancer, but they may alter the gut microbiome, which could influence the effectiveness of immune checkpoint inhibitors used to treat advanced non‐small cell lung cancer. Many previous studies compared proton pump inhibitor users with patients who did not use proton pump inhibitors. However, the choice of comparison group may affect the estimated association because patients who receive acid‐suppressive therapy may differ from non‐users in their underlying conditions, gastrointestinal symptoms, medication use, and clinical status. To address this issue, we compared proton pump inhibitor users with histamine‐2 receptor antagonist users as an active comparator, because both groups received acid‐suppressive therapy for overlapping indications. Using a large Japanese real‐world database, we found no clear difference in recorded mortality between proton pump inhibitor and histamine‐2 receptor antagonist users receiving immune checkpoint inhibitor–based therapy. In contrast, proton pump inhibitor use was associated with higher recorded mortality when compared with patients receiving neither proton pump inhibitors nor histamine‐2 receptor antagonists. These findings highlight the importance of selecting an appropriate comparison group when evaluating the association between proton pump inhibitor use and outcomes during immune checkpoint inhibitor therapy.
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      – SubjectFull: Histamine H2 Antagonists administration & dosage
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        Type: general
      – SubjectFull: Histamine H2 Antagonists therapeutic use
        Type: general
      – SubjectFull: Databases, Factual statistics & numerical data
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Female
        Type: general
      – SubjectFull: Retrospective Studies
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Aged
        Type: general
      – SubjectFull: Middle Aged
        Type: general
      – SubjectFull: Aged, 80 and over
        Type: general
      – SubjectFull: Proportional Hazards Models
        Type: general
      – SubjectFull: Propensity Score
        Type: general
      – SubjectFull: Cohort Studies
        Type: general
      – SubjectFull: Proton Pump Inhibitors adverse effects
        Type: general
      – SubjectFull: Proton Pump Inhibitors administration & dosage
        Type: general
      – SubjectFull: Proton Pump Inhibitors therapeutic use
        Type: general
      – SubjectFull: Carcinoma, Non-Small-Cell Lung drug therapy
        Type: general
      – SubjectFull: Carcinoma, Non-Small-Cell Lung mortality
        Type: general
      – SubjectFull: Carcinoma, Non-Small-Cell Lung pathology
        Type: general
      – SubjectFull: Lung Neoplasms drug therapy
        Type: general
      – SubjectFull: Lung Neoplasms mortality
        Type: general
      – SubjectFull: Lung Neoplasms pathology
        Type: general
      – SubjectFull: Immune Checkpoint Inhibitors therapeutic use
        Type: general
      – SubjectFull: Immune Checkpoint Inhibitors administration & dosage
        Type: general
    Titles:
      – TitleFull: Active and Non-Active Comparators Yield Different Estimates of the Association Between Proton Pump Inhibitor Use and Recorded Mortality During Immune Checkpoint Inhibitor Therapy for Advanced Non-Small Cell Lung Cancer.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Ihara Y
      – PersonEntity:
          Name:
            NameFull: Okada N
      – PersonEntity:
          Name:
            NameFull: Mizutani M
      – PersonEntity:
          Name:
            NameFull: Nakamura Y
      – PersonEntity:
          Name:
            NameFull: Shimomura Y
      – PersonEntity:
          Name:
            NameFull: Yamamoto S
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 09
              Text: 2026 Sep
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 1099-1557
          Numbering:
            – Type: volume
              Value: 35
            – Type: issue
              Value: 9
          Titles:
            – TitleFull: Pharmacoepidemiology and drug safety
              Type: main
ResultId 1