{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:00:41Z","timestamp":1792000841065,"version":"4.4.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,12,20]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Since July 2018, numerous lots of valsartan have been found to be contaminated with\n              <jats:italic>N<\/jats:italic>\n              \u2010nitrosodimethylamine (NDMA). We aimed to assess the association between exposure to valsartan products contaminated with NDMA and the risk of cancer.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">This study was based on data from the Syst\u00e8me National des Donn\u00e9es de Sant\u00e9, which is a national database that includes all French residents' health\u2010related expenses. The target population was consumers of valsartan between January 1, 2013 and December 31, 2017, aged between 40 and 80\u2009years old. The association of exposure to contaminated valsartan with the occurrence of any malignancy and cancer by location was evaluated by fitting Cox proportional hazards models weighted by the inverse probability of treatment. A total of 1.4 million subjects without any history of cancer were included. A total of 986\u2009126 and 670\u2009388 patients were exposed to NDMA\u2010contaminated and uncontaminated valsartan, respectively. The use of the NDMA\u2010contaminated valsartan did not increase the overall risk of cancer (adjusted hazard ratio [aHR], 0.99 [95% CI, 0.98\u20131.0]). However, exposed patients had a higher risk of liver cancer (aHR, 1.12 [95% CI, 1.04\u20131.22]) and melanoma (aHR, 1.10 [95% CI, 1.03\u20131.18]). We estimated a mean of 3.7 and 5.8 extra cases per year per 100\u2009000 person\u2010years of liver cancer and melanoma, respectively.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Our study was the largest to date to examine cancer risks associated with exposure to NDMA\u2010contaminated valsartan. Our findings suggest a slight increased risk of liver cancer and melanoma in patients exposed to NDMA in regularly taken medications.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.026739","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T11:01:17Z","timestamp":1671447677000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["<i>N<\/i>\n            \u2010nitrosodimethylamine\u2010Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-8695","authenticated-orcid":false,"given":"Im\u00e8ne","family":"Mansouri","sequence":"first","affiliation":[{"name":"EPI\u2010PHARE (French National Agency for Medicines and Health Products Safety [ANSM] and French National Health Insurance [CNAM]) Saint\u2010Denis France"},{"name":"Center for Research Epidemiology and Population Health (CESP), Radiation Epidemiology Team Universit\u00e9 Paris\u2010Saclay, Universit\u00e9 Paris\u2010Sud, UVSQ Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4814-6370","authenticated-orcid":false,"given":"Jeremie","family":"Botton","sequence":"additional","affiliation":[{"name":"EPI\u2010PHARE (French National Agency for Medicines and Health Products Safety [ANSM] and French National Health Insurance [CNAM]) Saint\u2010Denis France"},{"name":"Facult\u00e9 de Pharmacie Universit\u00e9 Paris\u2010Saclay Ch\u00e2tenay\u2010Malabry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-3487","authenticated-orcid":false,"given":"Laura","family":"Semenzato","sequence":"additional","affiliation":[{"name":"EPI\u2010PHARE (French National Agency for Medicines and Health Products Safety [ANSM] and French National Health Insurance [CNAM]) Saint\u2010Denis France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Haddy","sequence":"additional","affiliation":[{"name":"Center for Research Epidemiology and Population Health (CESP), Radiation Epidemiology Team Universit\u00e9 Paris\u2010Saclay, Universit\u00e9 Paris\u2010Sud, UVSQ Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Zureik","sequence":"additional","affiliation":[{"name":"EPI\u2010PHARE (French National Agency for Medicines and Health Products Safety [ANSM] and French National Health Insurance [CNAM]) Saint\u2010Denis France"},{"name":"Anti Infective Evasion and Pharmacoepidemiology Center for Research Epidemiology and Population Health (CESP) Montigny\u2010le\u2010Bretonneu France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.podrm.2015.01.004"},{"key":"e_1_3_1_3_2","unstructured":"French National Agency for Medicines and Health Products Safety . New valsartan medicine recalls: List of medicines concerned. Available at: https:\/\/ansm.sante.fr\/uploads\/2021\/01\/08\/2019\u201005\u201029\u2010liste\u2010sartans\u2010concernes.pdf. 2019."},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2019.04.035"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k3851"},{"key":"e_1_3_1_6_2","volume-title":"US Environmental Protection Agency (EPA). Technical Fact Sheet \u2013 NDMA","year":"2017","unstructured":"US Environmental Protection Agency (EPA). Technical Fact Sheet \u2013 NDMA. Washington, DC: US Environmental Protection Agency. Available at: https:\/\/www.epa.gov\/sites\/production\/files\/2017\u201010\/documents\/ndma_fact_sheet_update_9\u201015\u201017_508.pdf; 2017."},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/risa.12070"},{"key":"e_1_3_1_8_2","first-page":"1","article-title":"IARC monographs on the evaluation of carcinogenic risks to humans. Ingested nitrate and nitrite, and cyanobacterial peptide toxins","volume":"94","author":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans","year":"2010","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans . IARC monographs on the evaluation of carcinogenic risks to humans. Ingested nitrate and nitrite, and cyanobacterial peptide toxins. IARC Monogr Eval Carcinog Risks Hum. 2010;94:1\u2013412.","journal-title":"IARC Monogr Eval Carcinog Risks Hum"},{"key":"e_1_3_1_9_2","unstructured":"United States Environmental Protection Agency EPA . Six\u2010Year Review 3 Technical Support Document for Nitrosamines. Available at: https:\/\/www.epa.gov\/sites\/production\/files\/2016\u201012\/documents\/810r16009.pdf. 2016."},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(01)00301-3"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1967.65"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1520\/JFS11305J"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-10-8-1144"},{"key":"e_1_3_1_14_2","first-page":"25","volume-title":"Pathological Changes in Human Beings Acutely Poisoned by Dimethylnitrosamine","author":"Kimbrough RD","year":"1982","unstructured":"Kimbrough RD. Pathological Changes in Human Beings Acutely Poisoned by Dimethylnitrosamine. Banbury Report (USA). Vol. 12. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1982:25\u201336."},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0274(199903)35:3<264::AID-AJIM6>3.0.CO;2-X"},{"key":"e_1_3_1_16_2","unstructured":"Annual Report of the French National Agency for Medicines and Health Products Safety. Available at: https:\/\/www.ansm.sante.fr\/var\/ansm_site\/storage\/original\/application\/4a4914f30cd19e61213177e4d06fd1e4.pdf. 2018."},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/2042098618823458"},{"key":"e_1_3_1_18_2","volume-title":"The Sartan Contamination Story","author":"Lowe D","unstructured":"Lowe D. The Sartan Contamination Story. In the pipeline. Science Translational Medicine. January 4, 2019. Available at: https:\/\/blogs.sciencemag.org\/pipeline\/archives\/2019\/01\/04\/the\u2010sartan\u2010contamination\u2010story"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.m2021.0129"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/pds.4233"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.120.16314"},{"key":"e_1_3_1_22_2","volume-title":"New Valsartan Medicine Recalls: List of Medicines Non Concerned by Recalls","year":"2019","unstructured":"New Valsartan Medicine Recalls: List of Medicines Non Concerned by Recalls. French National Agency for Medicines and Health Products Safety (France). Available at: https:\/\/ansm.sante.fr\/uploads\/2021\/01\/07\/valsartan\u2010medicament\u2010non\u2010concernes\u20102019\u201011\u201001\u20102.pdf. 2019."},{"key":"e_1_3_1_23_2","unstructured":"French National Cancer Institute (INCa) . Cancer Algorithm. Available at: https:\/\/lesdonnees.e\u2010cancer.fr\/Informations\/Methodes\/Methode\u2010algorithme\u2010cancer2. 2017."},{"key":"e_1_3_1_24_2","unstructured":"French National Cancer Institute (INCa) . Algorithm for selecting hospitalizations related to cancer: validation study. Available at: https:\/\/www.e\u2010cancer.fr\/content\/download\/223512\/3046762\/file\/Algorithme_selection_hospitalisations_liees_au_cancer_en_MCO_Etude_de_validation_mel_20180201.pdf. 2018."},{"key":"e_1_3_1_25_2","unstructured":"Christine Le Bihan\u2010Benjamin LP Loubna Amal Estelle M\u00e9nard Mathieu Rocchi Bousquet PJ. Algorithme de s\u00e9lection des hospitalisations li\u00e9es au cancer en MCO: \u00e9tude de validation. French National Cancer Institut. Available at: https:\/\/www.e\u2010cancer.fr\/content\/download\/223512\/3046762\/file\/Algorithme_selection_hospitalisations_liees_au_cancer_en_MCO_Etude_de_validation_mel_20180201.pdf. 2018."},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0206448"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/70.1.41"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-4733.2009.00671.x"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6607"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/1467-9868.00346"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c02120"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.10043"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwp107"},{"key":"e_1_3_1_35_2","unstructured":"European Medicines Agency . Update on review of recalled valsartan medicines: preliminary assessment of possible risk to patients. Available at: https:\/\/www.ema.europa.eu\/en\/news\/update\u2010review\u2010recalled\u2010valsartan\u2010medicines\u2010preliminary\u2010assessment\u2010possible\u2010risk\u2010patients. 2018."},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.3889\/oamjms.2018.517"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.15226\/2378-1726\/7\/5\/001127"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(90)90064-N"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.37.4.383"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1515\/intox-2015-0001"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1272-8"},{"key":"e_1_3_1_42_2","first-page":"627","article-title":"Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20\u2009weeks) and of species (rats, mice or hamsters)","volume":"57","author":"Peto R","year":"1984","unstructured":"Peto R, Gray R, Brantom P, Grasso P. Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20\u2009weeks) and of species (rats, mice or hamsters). IARC Sci Publ. 1984;57:627\u2013665.","journal-title":"IARC Sci Publ"},{"key":"e_1_3_1_43_2","first-page":"6415","article-title":"Effects on 4080 rats of chronic ingestion of N\u2010nitrosodiethylamine or N\u2010nitrosodimethylamine: a detailed dose\u2010response study","volume":"51","author":"Peto R","year":"1991","unstructured":"Peto R, Gray R, Brantom P, Grasso P. Effects on 4080 rats of chronic ingestion of N\u2010nitrosodiethylamine or N\u2010nitrosodimethylamine: a detailed dose\u2010response study. Cancer Res. 1991;51:6415\u20136451.","journal-title":"Cancer Res"},{"key":"e_1_3_1_44_2","unstructured":"U.S. Food and Drug Administration . Laboratory analysis of valsartan products. https:\/\/www.fda.gov\/drugs\/drug\u2010safety\u2010and\u2010availability\/laboratory\u2010analysis\u2010valsartan\u2010products. 2019."},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2019.01.007"},{"key":"e_1_3_1_46_2","unstructured":"European Medicines Agency (EMA) . Lessons Learnt from Presence of N\u2010nitrosamine Impurities in Sartan Medicines. Available at: https:\/\/www.ema.europa.eu\/en\/documents\/report\/lessons\u2010learnt\u2010presence\u2010n\u2010nitrosamine\u2010impurities\u2010sartan\u2010medicines_en.pdfTaggedEnd. 2020."},{"key":"e_1_3_1_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-010-0119-y"},{"key":"e_1_3_1_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.044494"},{"key":"e_1_3_1_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.02.034"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.122.026739","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T12:38:50Z","timestamp":1715603930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.122.026739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,20]]},"references-count":48,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2022,12,20]]}},"alternative-id":["10.1161\/JAHA.122.026739"],"URL":"https:\/\/doi.org\/10.1161\/jaha.122.026739","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,20]]},"assertion":[{"value":"2022-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e8067"}}