Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition

Table 1 The conclusion of the studies reviewed

Study	Setting	Studies	Participants	Ascertainment of statin use for inclusion	Risk estimates for statins (vs no statin) and factors adjusted for	Limitations, notes and quality
Kastelein et al[25]	Netherlands, hospital based	Prospective cohort	Cohort of 570 BO, 38 developed EAC or HGD	All statins, statin use during study period, patient interview and questionnaire, pharmacy records	Statin use = 1 mo HR = 0.46 (95%CI: 0.21-0.99); statin use = 5 yr HR = 0.51 (018-0.1.47); statin use = 5 yr HR = 0.49 (95%CI: 0.22-0.85); statin plus aspirin HR = 0.22 (95%CI: 0.06-0.85); adjusted for age, sex, length of BO, baseline histology and aspirin use	No adjustment for BMI or smoking; limited categorisation of duration-, and dose-relationship; Newcastle-Ottawa 9 stars
Nguyen et al[24]	United States, hospital based, veterans administration	Case-control	116 EAC, 696 BO	All statins, at least 1 filled statin prescription in study period, pharmacy database	At least 1 statin prescription HR = 0.56 (95%CI: 0.36-0.87); statin use < 12 mo HR = 0.63 (95%CI: 0.38-1.06); statin use > 12 mo HR = 0.52 (95%CI: 0.30-0.91); adjusted for race, out-patient encounters, non-cancer co-morbidity, use of other medications	97% male, veterans’ population; Not adjusted for BMI, alcohol, smoking; no categorisation of dose-relationship; Newcastle-Ottawa 9 stars
Beales et al[26]	United Kingdom, hospital based	Case-control	85 EAC, 170 BO	All statins, statin use for > 6 mo prior to cancer diagnosis, questionnaire and clinical and prescribing records	Statin use OR = 0.57 (0.28-0.94); statin and aspirin combined OR = 0.31 (95%CI: 0.04-0.69); adjusted for age, sex, smoking, aspirin, NSAIDs, proton pump inhibitors, BMI, diabetes mellitus, metformin, alcohol; significant negative associations with statin dose and duration.	Cancers were a mix of de novo and screening-detected cancers; Newcastle-Ottawa 8 stars
Beales et al[34]	United Kingdom, hospital based	Case-control	112 EAC, 448 cancer negative gastroenterology outpatients	All statins, statin use for > 6 mo prior to cancer diagnosis, questionnaire and clinical and prescribing records	Statin use OR = 0.52 (95%CI: 0.27-0.92); statin and aspirin combined OR 0.27 (95%CI: 0.05-0.67); adjusted for age, sex, smoking, aspirin, NSAIDs, proton pump inhibitors, BMI, alcohol, diabetes mellitus, metformin; United Kingdom, population based	Controls were hospital outpatients; Newcastle-Ottawa 8 stars
Fang et al[12]	United Kingdom, hospital based	Case-control	EAC 63, cancer-negative gastroenterology outpatients 252	All statins, statin use for > 6 mo prior to cancer diagnosis, questionnaire and clinical and prescribing records	Unadjusted statin OR = 0.42 (95%CI: 0.19-0.89); unadjusted statin plus aspirin OR = 0.11 (95%CI: 0.01-0.82)	Controls were hospital outpatients. Unadjusted for any risk factors; not included in meta-analysis as more extensive dataset published subsequently; not quality rated
Kantor et al[18]	United States	Prospective cohort	BO 411 in cohort, EAC developed in 56	All statins, any statin use during study period, questionnaire	Statin use OR = 0.68 (95%CI: 0.30-1.54); adjusted for sex, age, smoking, NSAIDs	No adjustment for BMI; no data on dose or duration relationship. Included any use of statin, Relatively low incidence of statin use in BO population; Newcastle-Ottawa 9 stars
Nguyen et al[17]	United States, hospital based, veterans administration	Retrospective cohort	BO 344 in cohort, EAC or HGD developed in 33	All statins, any statin prescription during the period of study, pharmacy and clinical records	Statin use OR = 0.73 (95%CI: 0.30-1.78), unadjusted	94% male, veterans population. Incomplete adjustment for potential confounding factors; Newcastle-Ottawa 8 stars
Bhutta et al[32]	United Kingdom, population based	Case-control	4242 cancers, 17233 controls	All statins, statin prescription for 10 mo in the year preceding diagnosis of cancer; read codes within GPRD	Use of statins OR = 0.84 (95%CI: 0.73-0.95); adjusted for BMI, smoking, aspirin, NSAIDs, proton pump inhibitors, vasodilators	No categorisation of statin dose; related to Hippisley-Cox 2010 but different methodology to interrogate the same research database; Newcastle-Ottawa 9 stars
Vinograd ova et al[28]	United Kingdom, population based	Case-control	3159 cancers, 13041 controls	All statins, statin use as defined by 2 prescriptions over a 5 year period at least 12 mo prior to cancer diagnosis; read codes within QResearch database	Use of statins OR = 0.88 (95%CI: 0.77-1.01); adjusted for Townsend score, smoking, circulatory disease, diabetes mellitus, rheumatoid arthritis, COX-2 inhibitors	Data for EAC and ESC combined; no individual confirmation of pathology. No categorisation of statin dose; related to Hippisley-Cox 2010 but different methodology to interrogate the same research database; Newcastle-Ottawa 9 stars
Hippisley-Cox et al[31]	United Kingdom, population based	Prospective cohort	1809 cancers, 2004692 overall participants	All statins, new users of statins defined by a new statin prescription in the study period; read codes within QResearch database	Men, statin HR = 0.78 (95%CI: 0.66-0.91); women, statin HR 0.68 (95%CI: 0.52-0.88); adjusted for, age, BMI, smoking, townsend score, type 2 diabetes	Data for EAC and ESC combined. No individual confirmation of pathology; no adjustment for aspirin or NSAIDs; no data on duration or long term statin exposure; Newcastle-Ottawa 9 stars
Kaye et al[29]	United Kingdom, population based	Case-control	100 cancers, 430 controls	All statins, current use defined as a statin prescription that started within 12 mo of cancer diagnosis; read codes within GPRD	Statin use OR = 0.80 (95%CI: 0.30-1.80); adjusted for smoking, BMI, number of GP visits	Data for EAC and ESC combined. No individual confirmation of pathology; no adjustment for aspirin or NSAIDs; no data on duration or long term statin exposure; Newcastle-Ottawa 9 stars
Friedman et al[30]	United States, population based	Retrospective cohort	68 cancers, 4413032 controls	All statin, any statin use prior to cancer diagnosis, Kaiser Permanente Cancer Registry and Pharmacy management systems	Overall unadjusted statin use OR = 1.0 (95%CI: 0.77-1.27); men with > 5 yr statin use OR = 1.70 (95%CI: 1.05-12.75).	Data for EAC and ESC combined; no individual confirmation of pathology; no dose-effect relationship examined; no correction for confounding variables; small number of cancers; Newcastle-Ottawa 9 stars
Lai et al[27]	Taiwan, population based	Case-control	549 cancers, 2196 controls.	All statins, statin prescription prior to cancer diagnosis; data from Taiwanese NHI programme	Statin use OR = 0.66 (0.45-0.95); atorvastatin = 12 mo OR = 0.14 (95%CI: 0.04-0.56); adjusted for esophageal diseases, H. pylori infection, alcoholism, smoking, lipid lowering drugs, proton pump inhibitors, H2RA, NSAIDs and aspirin	Data for EAC and ESC combined; no individual confirmation of pathology; no dose-effect relationship examined; Newcastle-Ottawa 9 stars
Bhutta et al[33]	United Kingdom, population based	Case-control	Not clearly defined	Not clearly defined; read codes within general practice research database	Statin use OR for EAC 0.61 (95%CI: 0.35-0.94), OR for ESC (95%CI: 0.21-0.80); unclear what adjustments applied	No individual confirmation of pathology; insufficient data for inclusion in meta-analysis appears to be essentially the same cohort as Bhutta 2011; no response from author when asked for further information; not quality rated or included

EAC: Esophageal adenocarcinoma; HGD: High-grade dysplasia; ESC: Esophageal squamous cell cancer; H2RA: Histamine-2 receptor antagonist; NSAIDs: Non-steroidal anti-inflammatory drug; H. pylori: Helicobacter pylori; NHI: National Health Insurance; BMI: Body mass index; COX-2: Cyclooxygenase-2.