Epidemiology of non-steroidal anti-inflammatory drugs consumption in Spain.The MCC-Spain studyInés Gómez-Acebo1,2*, Trinidad Dierssen-Sotos1,2, María de Pedro2,3, Beatriz Pérez-Gómez1,4,5,Gemma Castaño-Vinyals1,6,7,8, Tania Fernández-Villa9, Camilo Palazuelos-Calderón2, Pilar Amiano1,10,Jaione Etxeberria1,11, Yolanda Benavente1,12, Guillermo Fernández-Tardón1,13, Inmaculada Salcedo-Bellido1,14,Rocío Capelo15, Rosana Peiró1,16, Rafael Marcos-Gragera1,17, José M. Huerta1,18, Adonina Tardón1,13,Aurelio Barricarte1,19,20, Jone-Miren Altzibar1,21, Jessica Alonso-Molero2, Verónica Dávila-Batista9,Nuria Aragonés1,4,5,22, Marina Pollán1,4,5, Manolis Kogevinas1,6,7,8 and Javier Llorca1,2
Abstract
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used despite their risk of gastrointestinalbleeding or cardiovascular events. We report the profile of people taking NSAIDs in Spain, and we includedemographic factors, health-related behaviours and cardiovascular disease history.
Methods: Four thousand sixtyparticipants were selected using a pseudorandom number list from Family Practicelists in 12 Spanish provinces. They completed a face-to-face computerized interview on their NSAID consumption,demographic characteristics, body mass index, alcohol and tobacco consumption and medical history. In addition,participants completed a self-administered food-frequency and alcohol consumption questionnaire. Factorsassociated with ever and current NSAID consumption were identified by logistic regression.
Results: Women consumed more non-aspirin NSAIDs (38.8% [36.7–41.0]) than men (22.3 [20.5–24.2]), but menconsumed more aspirin (11.7% [10.3–13.2]) than women (5.2% [4.3–6.3]). Consumption of non-aspirin NSAIDs decreasewith age from 44.2% (39.4–49.1) in younger than 45 to 21.1% (18.3–24.2) in older than 75, but the age-pattern foraspirin usage was the opposite. Aspirin was reported by about 11% patients, as being twice as used in men (11.7%)than in women (5.2%); its consumption increased with age from 1.7% (< 45 years old) to 12.4% (≥75 years old). Aspirinwas strongly associated with the presence of cardiovascular risk factors or established cardiovascular disease, reachingodds ratios of 15.2 (7.4–31.2) in women with acute coronary syndrome, 13.3 (6.2–28.3) in women with strokes and 11.1(7.8–15.9) in men with acute coronary syndrome. Participants with cardiovascular risk factors or diseases consumed asmuch non-aspirin NSAID as participants without such conditions.
Conclusions: Non-aspirin NSAIDs were more consumed by women and aspirin by men. The age patterns of aspirinand non-aspirin NSAIDs were opposite: the higher the age, the lower the non-aspirin NSAIDs usage and the higher theaspirin consumption. People with cardiovascular risk factors or diseases consumed more aspirin, but they did notdecrease their non-aspirin NSAIDs usage.
* Correspondence: [email protected] Epidemiología y Salud Pública, Madrid, Spain2Facultad de Medicina, Universidad de Cantabria – IDIVAL, Avda Herrera Orias/n, 39011 Santander, SpainFull list of author information is available at the end of the article
BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are one ofthe most used therapeutic groups of agents; they can be ob-tained over-the-counter in many countries, and they areused for a wide variety of indications, including short-termand long-term treatment of pain, traumatisms, inflammatorydiseases such as arthritis, rheumatoid arthritis and manyothers. On the other hand, NSAIDs can be responsible forseveral well-known side effects, comprising upper gastro-intestinal bleeding [1] and cardiovascular disease [2]. Whilegastrointestinal haemorrhage would partially be preventedby adding proton-pump inhibitors to NSAIDs [3, 4], there isstill some controversy regarding the differences in cardiovas-cular risk among the NSAID family [5].Although the consumption of NSAIDs in Spain has de-
creased from 43.1 in the year 2013 to 37.9 in 2016, and thisdecrease in consumption was observed in all subgroups [6];some studies have shown a trend towards increasingNSAID usage in developed countries [7, 8]. Little is known,however, about the medical characteristics of the con-sumers. In this way, medical records would be insufficientto establish patient profile, as a relevant NSAID amount istraded over-the-counter. Demographic characteristics areassociated with different adverse effect risks. For instance,gastrointestinal haemorrhage is more frequent in elderpeople taking NSAIDs than in youngsters [1], and similarconsiderations could are responsible for cardiovascular ef-fects [2]. Moreover, some health-related behaviours, such asalcohol [9] or -we speculate- tobacco usage, if associatedwith NSAID consumption, could potentiate their risk ofcardiovascular episodes or gastrointestinal bleeding. Thus,Chi et al. observed that the proportions of patients withconcomitant antiplatelet drugs, H pylori infection and sta-tus of smoking were also considerably higher in GI (gastro-intestinal) bleeding group compared to non-GI bleedinggroup GI bleeding group associated with NSAIDs drugs[10] and Sostres et al. also observed that a higher risk ofupper GI bleeding was associated with current or pastsmoking habit and previous history of peptic ulcer [11].The aim of this study is to describe demographic char-
acteristics related to NSAID consumption in the adultpopulation in Spain, as well as health-related behaviorsand cardiovascular risk factors. In order to do this, weanalysed the control sample (about 4000 subjects) in theMCC-Spain project, a multi-centre case-control studycarried out in Spain.
MethodsMCC-Spain is a case-control study on cancer carried out in12 Spanish provinces: Asturias, Barcelona, Cantabria, Gi-rona, Granada, Gipuzkoa, Huelva, León, Madrid, Murcia,Navarra, and Valencia [12]. More than 10,000 patients wererecruited from 2009 to 2012, including cases of colorectal,breast, prostate or gastric cancer, and chronic lymphoid
leukaemia, and 4062 controls frequency matched by age, sexand area of recruitment. In this article, only the control sam-ple will be analysed, so all references to patients, subjects orparticipants from here on refer to the control sample. Thestudy design, sample size and data gathering were plannedfor the case-control study.Participants were recruited using computer-generated
pseudorandom numbers from the list of patients assignedto general practice clinics. Selected people were contactedby phone; if contact with the selected person was not pos-sible after a minimum of five tries at different times of theday, or if he/she refused to participate, the following personon the list was approached. In the Spanish Health System,every inhabitant is assigned to a general practice clinic irre-spective of whether he or she does attend to that clinic;therefore, selecting by random from those lists did notintroduce a bias towards sick people. Participants whoagreed to partake in the study signed an informed consentbefore the face-to-face interview, and the protocol ofMCC-Spain was approved by the local Ethics Committeesof participating institutions (Comité Ético de InvestigaciónClínica (CEIC) del Instituto Municipal de Asistencia Sani-taria de Barcelona; CEIC del Hospital Universitario de Bell-vitge; CEIC de Navarra; CEIC del Hospital Universitario LaPaz; CEIC del Hospital Universitario Ramón y Cajal; CEICde Cantabria; CEIC de Gipuzkoa; CEIC de Girona; Comitéde Ética de la Investigación de la Provincia de Huelva; CEICde León; Comité Ético de Investigación del Principado deAsturias), in conformity to the principles of the Declarationof Helsinki. The database was registered in the SpanishAgency for Data Protection (no. 2102672171).A structured computerized epidemiological questionnaire
was administered by trained personnel in a face-to-faceinterview to get information on demographics, anthropo-metrics, family history of cancer, history of diseases, drugconsumption, occupational history, health behaviours, andreproductive factors [13]. Usage of NSAIDs was specificallyasked about using a detailed questionnaire including thespecific NSAID, age at beginning, age when end duration ofconsumption and current consumption; a participant wasconsidered as having taken a specific NSAID if she/hereported to have taken at least 30 doses. We carried out sep-arated analyses for ever and current consumers of NSAIDs;current consumption could be consequence of recentconditions, while ever consumption better representscumulative exposure to NSAIDs but it could be moreprone to recall bias.On the other hand, participants were provided with a
semi-quantitative Food Frequency Questionnaire (FFQ) pre-viously validated in the Spanish population [14], whichincluded questions on alcohol consumption both currentlyand at 30–40 years old [15]. The FFQ was self-administeredand returned by mail or filled out face to face within aperiod not exceeding 15 days after the interview [13]. Only
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3509 participants answered this questionnaire. Alcoholconsumption was asked for every type of beverage; for in-stance, we asked “How often do you drink one glass of redwine?”, giving the options: never or less than 1 time permonth / 1–3 per month / 1–2 per week / 3–4 per week /5–6 per week / 1 per day / 2–3 per day / 2–3 per day / 4or more per day. Then we assumed a glass of wine being100 cL, containing 12% alcohol. Average alcohol drinkingwas classified in abstainer (less than one drink per month),category I (0–19.9 g /day for women and 0–39.9 g/day formen), category II (20–39.9 g/day for women, 40–59.9 g/day for men) and category III (≥40 g/day for women,≥60 g/day for men), according to the comparative risk as-sessment module of the Global Burden of Disease [16].For instance, it would be necessary to take 4 glasses ofwine or 2 cups of whisky to reach 40 g of alcohol. NSAIDswere classified according to the Anatomical and Thera-peutic Classification of Drugs (ATC) in aspirin (ATC codeN02BA01), butilpirazone (M01aa), acetic derivatives(M01ab), oxicams (M01 ac), propionates (M01ae), coxibs(M01ah) and others (M01ax).A separated analysis was carried out to ascertain
NSAID consumption in people with cardiovascular dis-eases or risk factors, as current clinical guidelines pointout the increase of cardiovascular risk associated withnon-aspirin NSAIDs.Proportions and their 95% confidence intervals (CI)
were estimated assuming a binomial distribution. Vari-ables associated with NSAID consumption were identi-fied by binomial logistic regression; its results aredisplayed as odds ratios (OR) with 95% CI. The statis-tical package Stata 14/SE was used for the analysis (StataCorp, College Station, Tx, US).
ResultsCharacteristics of the 4060 controls included in this ana-lysis are reported in Table 1. They were 2023 women and2037 men, with ages ranging 22–85; 49.4% had reachedsecondary or university education. 61.8% subjects wereoverweight or obese, 19.2% were current smokers and,when being 30–40 years old, 16% had an average alcoholconsumption higher than 20 g/day in women and 40 g/day in men. About one participant in four suffered arth-ritis, 10% had chronic cephalalgia and 5.6%, gout. Arthritisand chronic cephalalgia were more frequent in women.Figure 1 and Additional file 1 reported the ever NSAID
consumption frequency by age and sex. About 30% subjectsreported non-aspirin NSAID consumption, showing astep-down trend with age, from 44.2% in subjects under 45to 21.1% in patients over 75. Women consumed NSAID athigher rates than men (38.8% vs. 22.3%); this gender patternwas consistent among all ages. The most consumed NSAIDgroup was propionates (M01ae) (29.2%) with, again, a con-sistent age and sex pattern: higher consumption in women
and in youngsters. Aspirin was reported by about 11% pa-tients, being twice as used in men (11.7%) than inwomen (5.2%); its consumption increased with agefrom 1.7% (< 45 years old) to 12.4% (≥75 years old).Acetate derivatives (M01ab) -the third most con-sumed group- was reported in similar percentages byboth sexes, without a neat trend with age. Consump-tion of the remaining groups was scarce (butylpyrazo-lidines (M01aa): 0.03%, oxicam (M01 ac): 0.6%, coxib(M01ah): 0.6%, others (M01ax): 2.19%) and we didnot carry out additional analyses on them. Consump-tion of NSAIDs at the time of recruitment is reported inFig. 2 and Additional file 2. Women used non-aspirinNSAIDs twice as much as men (20.7% for women vs. 9.0%for men); again, this pattern was consistent across agegroups, with non-aspirin NSAID consumption decreasingfrom 22.1% in younger than 45 years to 10.4% in older than75. Aspirin, however, was more consumed by men (9.0%)than for women (2.9%) and its rates increased with age inboth men and women. About two thirds of the non-aspirinNSAID consumption was due to propionates; in men, theconsumption declined from 9.4% in younger than 45 yearsold to 2.7% in men older than 75; in women, the decreasewas from 20.7% (< 45 years) to 9.4% (> 75 years).Consumption by province (Additional file 3) was het-
erogeneous ranging from 13.4% (in Granada) to 45.1% inGirona) for non-aspirin NSAIDs.The most frequently ever used specific NSAIDs were
ibuprofen (20.4%), aspirin (11%) and diclofenac (6.4%).Only three other drugs were used by more than 1% ofpeople: aciclofenac (1.5%), naproxen (1.4%) and chon-droitin sulphate (1.3%). Regarding current consumption,only ibuprofen (9.2%), aspirin (5.9%), diclofenac (2.0%)and chondroitin sulphate (1.0%) reached the 1% cut off(Additional file 4).
Factors related to NSAIDs ever consumptionTables 2, 3, 4 and 5 report the factors associated with con-sumption of the main NSAID groups in men and women,according to the multivariate logistic regression analysis.Non-aspirin NSAID were less consumed in men as age in-creased (reaching OR= 0.26 in men older than 75 comparedto men between 45 and 54 years old) and as education levelgoes up, being about twice as frequent in men with univer-sity level than in men without primary studies; no associ-ation was found among non-aspirin NSAID consumption inmen and body mass index (BMI)or ethanol consumption.However, men who currently use NSAIDs that are notaspirin were half less likely (OR = 0.49) to be currentsmokers than non-smokers. If we consider chronic diseaseinvolving pain, men who had arthritis multiplied by almost3 the probability of taking non-aspirin NSAID and doubledits use in other chronic disease involving pain that were notarthritis gout or chronic cephalalgia (Table 2). Similar
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Table 1 Descriptive analysis of sociodemographic variables
Other circulatory diseases 628 (15.5) 330 (16.4) 298 (14.7)
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patterns were found in women, although both age and edu-cation levels showed less apparent trends. Number of birthsand menopausal status were not associated with non-aspirinNSAIDs consumption. Patients with chronic conditions in-volving pain (arthritis, gout or chronic cephalalgia) con-sumed non-aspirin NSAIDs four times as much asparticipants without such conditions. In contrast than men,women who once used NSAIDs without aspirin were ap-proximately 38% more likely to be current smokers thannonsmokers and use in chronic cephalalgia (OR 2.54 forever or OR 1.66 for current use).As propionate derivatives were the more frequently
consumed NSAID group, its related factors (Table 3) re-sembled those of non-aspirin NSAIDs: the higher theage, the lower the propionate derivative consumption,and for men, the higher the education level, the higher
their propionate derivative consumption. People withconditions with chronic pain (arthritis, chronic cephalal-gia or gout) used propionate derivates twice or threetimes more frequently than people without such condi-tions. Multivariate results in aspirin consumptions aredisplayed in Table 4. Men increased their aspirin con-sumption with age, being about three times higher inmen older than 65, and smoking habit, with current orformer smokers having 60% higher aspirin consumptionthan non-smoking men. In women, however, only ageand number of births (OR = 1.24 for each birth) in-creased aspirin consumption.Factors associated with acetate derivates are analyzed
in Table 5. Chronic diseases involving pain multiplied by2.7 (women) and 3.5 (men) the odds of having used acet-ate derivates. Apart from this factor, in men, only the
Fig. 1 Anytime consumption of NSAID by age and sex. 1a: Aspirin and non-aspirin NSAID. 1b: Propionates and acetate derivates
Fig. 2 Current consumption of NSAID by age and sex. 1a: Aspirin and non-aspirin NSAID. 1b: Propionates and acetate derivates
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educational level reached a positive significant relationshipwith consumption; men with secondary or university edu-cation reported about twice the acetate derivative con-sumption than men with lower educational levels. No otherfactor can be identified as associated with acetate derivativeconsumption in women. BMI displayed a non-significantassociation in both men and women.
Factors related to current consumptionNon-aspirin NSAIDs consumption (Table 2) stepped downwith age in both women (OR= 1.17, 1, 0.62, 0.39 and 0.46for the ordered age groups) and men (OR= 1.57, 1, 1.27,0.76 and 0.37). Men with university level education
consumed twice as much as men with less-than-primarylevel; a similar result was not found in women. Consump-tion of non-aspirin NSAIDs was halved in current smokingmen. Regarding alcohol use, only participants in the highestcategory of current consumption (i.e.: ≥60 g/day for menand ≥ 40 g/day for women) reported higher non-aspirinNSAID used, although estimates were unstable for womendue to the small number of women in this category. Suffer-ing arthritis, gout or chronic cephalalgia multiplies the prob-ability of using non-aspirin NSAIDs by about 4.Propionates consumption (Table 3) in men went down
with age -reaching OR = 0.19 in men older than 75- andin current smokers (OR = 0.55). Suffering chronic pain
Table 2 Factors associated with non-aspirin NSAID consumption: odds ratios and 95% confidence intervals adjusted for theremaining factors in the table and province of recruitment
Variable Category Ever consumption Current consumption
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conditions (OR= 2.48) and having reached university level(OR = 2.00) were the only factors associated with higherpropionate used. In women, higher ages were also associatedwith lower propionate consumption (OR= 0.38 in women> 75 years) and the presence of chronic pain diseases, withhigher consumption (OR= 2.58); no other factor could beidentified as associated with this NSAID group.Higher age was a risk factor for using aspirin in both
women and men (Table 4), with OR for the elder groupreaching 6.8 (women) and 4.7 (men). The educationlevel was negatively associated with aspirin consumptionin women, but not in men, while smokers (both formerand current) were related with higher aspirin use in
men. Suffering from a chronic pain condition was notassociated with aspirin consumption.Apart from chronic pain diseases, which were associ-
ated with 3 or 4 times higher acetate derivate consump-tion (Table 5), only non-significant positive associationswere found between this NSAID group and alcoholconsumption (both sexes) and higher education level(men, but not women).
NSAID consumption and cardiovascular disease or riskfactorsTo further explore the risk profile of cardiovascular ad-verse events while taking NSAIDs, we analysed the
Table 3 Factors associated with propionate derivate consumption: odds ratios and 95% confidence intervals adjusted for theremaining factors in the table and province of recruitment
Variable Category Ever consumption Current consumption
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relationship between NSAID use and current cardiovascu-lar disease or risk factors. Results are shown in Table 6.Men with diabetes mellitus consumed less non-aspirinNSAIDs -and, specifically, less propionates- than menwithout that condition; no such result could befound for women. Having hypertension, hypercholes-terolemia or medical history of acute coronary syn-drome (i.e.: acute myocardial infarction or angina),stroke or other circulatory diseases was not associ-ated with lower non-aspirin NSAID consumption inany gender. Using aspirin, however, increased inboth women and men suffering any of these cardio-vascular risk factors or diseases, with OR as higher
as 15.2 (women with acute coronary syndrome), 13.3(women having had a stroke) or 11.1 (men withacute coronary syndrome).
DiscussionAccording to our results, NSAID consumption differedby gender and age, being aspirin more used by men andolder participants and propionates by women and theyoungsters. Consumption of any major NSAID groupwas consistently associated with educational level inmen: the higher the educational level, the higher theNSAID usage. Regarding health-related behaviours,current smoker women had ever consumed more
Table 4 Factors associated with aspirin consumption: odds ratios and 95% confidence intervals adjusted for the remaining factors inthe table and province of recruitment
Variable Category Ever consumption Current consumption
Women Men Women Men
Age < 45 0.62 (0.20–1.96) 0.25 (0.03–2.06) 0.76 (0.06–9.39) –
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non-aspirin NSAIDs but current smoker men had lowercurrent consumption of non-aspirin NSAIDs than nosmoker women and men, respectively. Higher currentconsumption was found in current heavy ethanoldrinkers. People with higher risk of cardiovascular ad-verse episodes when taking non-aspirin NSAIDs (i.e.:participants with cardiovascular disease history or car-diovascular risk factors) consumed as much non-aspirinNSAID as people without such a high risk, the only ex-ception being men with diabetes mellitus, who halvedthe non-aspirin NSAID current consumption. Nonethe-less, participants with higher cardiovascular risk took as-pirin more frequently.
Consumption compared with other countriesIbuprofen was by far the more consumed NSAID in ourstudy. Higher use of ibuprofen has also been informedin Germany [17], the US [18] and Denmark [19]. Astudy on 15 countries, however, reported diclofenac asthe most frequently used, followed by ibuprofen [20].Many articles have reported NSAID trend use [17, 21],which has not been analysed in our study. However, thetrend in Spain seemed to be rising until 2009 and slowlydecreasing from then on; specifically, ibuprofen reachingits zenith in 2009, while naproxen began to increase in2012 [22]. Qato et al. [7] informed of increases inNSAID drugs from 2005 to 2011 in the US, with aspirin
Table 5 Factors associated with acetate acid derivate consumption: odds ratios and 95% confidence intervals adjusted for theremaining factors in the table and province of recruitment
Variable Category Ever consumption Current consumption
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use increasing from 30.2 to 40.2% and other NSAIDsfrom 10.15 to 13.7%. Differences in definitions andmethodology among the studies, however, makes it diffi-cult to compare figures from different countries.
Patterns by age and sexFew studies reported NSAID pattern consumption byage. Like ours, Dale et al. [23] informed of an increase inaspirin and a decrease in other NSAIDs with age inNorway; Sarganas et al. [17] also reported that NSAIDconsumption was lower with higher age in Germany.Clinical guidelines recommend restricting non-aspirinNSAIDs in the older group because people at a higherage have higher risks of NSAID-related adverse episodes,both gastrointestinal haemorrhage and cardiovascularevents [1, 3], so our results are in accordance with this.The interpretation of the age-pattern of aspirin is challen-ging as its consumption would be as an analgesic/anti-in-flammatory drug or as anti-aggregant. In our study,aspirin was strongly associated with cardiovascular riskfactors, such as hypertension and hypercholesterolemia,
but especially with previous cardiovascular diseases, suchas acute coronary syndrome and strokes. Aspirin iswell-known as a drug able to produce gastrointestinalhaemorrhage, especially in aged people, but also for itscardiovascular protective effects when used in low doses.Being in no doubt of its usage for secondary prevention inpeople already affected by ischemic cardiovascular disease,current US Preventive Service Task Force [24] recom-mendation for cardiovascular disease primary preven-tion, however, only supports using aspirin in peopleaged between 50 and 59, with possible extension onindividual basis until 69 years old, but no longer asevidence of the risk/benefit relationship in patientsolder than 70 was considered insufficient [25].Women consumed more NSAIDs than men, as previ-ously reported in several articles [17, 23]. In ourstudy, arthritis and chronic cephalalgia were more fre-quent in women, confirming other studies which sug-gested that non-malignant chronic diseases causingpain are more prevalent in women [26], eventuallyleading to more analgesic / anti-inflammatory usage.
Table 6 Association between cardiovascular disease or risk factors and current NSAID consumption (odds ratios and 95%confidence intervals adjusted by age, BMI, educational level, smoking, province of recruitment and presence of arthritis, gout orchronic cephalalgia)
NSAID Cardiovascular disease or risk factor Women Men
Other circulatory diseases 1.53 (0.83–2.80) 0.97 (0.43–2.19)
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Education levelEducation level could be used as a surrogate forsocio-economic level. It was positively associated withNSAID use in our study. These results, however, are incontrary to those found in Germany [7, 17] which stud-ied education and house income as different variables withsimilar findings: a positive association with NSAIDs: thehigher the education level or the higher the house income,the more frequent the NSAID consumption is.
Health-related behavioursAmong currently smokers, we found that women hadhigher ever non-aspirin NSAIDs consumption and menhad lower current non-aspirin NSAIDs current or formersmoker men had consumed more aspirin. Current alcoholconsumption had a positive but non-significant associ-ation with non-aspirin NSAIDs. Dale et al. found a posi-tive association of NSAID consumption with currentsmoking and a negative one with alcohol [23], while bothalcohol and tobacco use were positively associated withNSAIDs in Sweden about 20 years previously [27]. As sug-gested in Dale et al., these differences may echo culturaland social changes throughout that period [23].
Differences in current and ever NSAID consumptionMost patterns of consumption were quite similar forcurrent and ever consumers. Non-aspirin NSAIDs weremore consumed by more educated men and women,while aspirin were more consumed by older people; thesepatterns were more marked in current than in ever con-sumers, which is probably indicating recent trends. To in-terpret differences among current and ever consumption,however, is speculative as data on both consumptions areprone to different biases; in this regard, we focused moreon similarities than on differences as similar patternscould be considered some kind of confirmatory results.
Public health implicationsRecommendations for prescribing NSAIDs have been de-veloped in guidelines [3, 4] regarding their risk profile ongastrointestinal haemorrhage and cardiovascular episodes.They agree in considering naproxen as being less prone tocardiovascular episodes than ibuprofen, thus they recom-mended using naproxen if a non-aspirin NSAID is neededin patients with high cardiovascular risk, especially if theyare taking aspirin for cardio-protection. However, theFDA (Food and Drug Administration), in a safety an-nouncement for advising on cardiovascular risks associ-ated with NSAIDs, stated there is not enough evidence todetermine that a specific non-aspirin NSAID has higheror lower cardiovascular risk than any other [5]. Therefore,the relevance of higher use of ibuprofen than naproxen-as we reported- is unclear. On the other hand, olderpeople, which are at high risk of cardiovascular events or
gastrointestinal haemorrhage, tend to use less non-aspirinNSAIDs and more aspirin than people at low risk. Finally,although the higher consumption of aspirin by peoplewith cardiovascular diseases or risk factors would be re-lated with its usage as secondary prevention, the fact thatthe same high cardiovascular risk people did not reportlower non-aspirin NSAID consumption brings up a pointof concern because these NSAIDs could put them athigher cardiovascular risk.
Strenghs and limitationsOur study has some limitations. Firstly, information onNSAID use was obtained in a face-to-face interview, so itwould be affected by recall bias and social desirability bias aswell; moreover, no information was recorded on prescrip-tions in order to validate whether the information providedin the interview accurately represented actual NSAID con-sumption. On the other hand, some subjects could considerthat drugs obtained over-the-counter -as occurs with manyNSAID, especially aspirin- are not really medicines, leadingto underreport their usage. Secondly, the sample is formedby the control group in a case-control study on several typesof cancer; although participants in the study were selected atrandom, some cancer cases had to be excluded. This factcould bias the results towards lower NSAID consumptionthan the general population. Thirdly, although our subjectswere selected at random, we cannot exclude that peopleagreeing to participate could be self-selected because of theirhealth behaviours or interests, which could limit thegeneralization of our results. Fourth, our data did not allowus to distinguish whether aspirin is being taken as painkilleror for cardiovascular prevention purposes.By the other hand, our study has also some strengths
within his study. Firstly, we have a large sample from 12different Spanish provinces, which makes our resultsmore reliable. Secondly, the vast amount of informationgathered as part of a case-control study on cancer allowsus the analysis of determinants of NSAID consumption.It is noteworthy that participants were not aware of anyhypothesis regarding NSAID usage when they wereinterviewed, which makes unlikely the presence of differ-ential biases associated with the reported informations.
ConclusionSummarizing, we found that propionates are the mostconsumed group of NSAIDs in Spain. Consumption ofnon-aspirin NSAIDs was associated with demographicgroups with lower gastrointestinal and cardiovascularrisk; however, participants at high cardiovascular riskhad no lower non-aspirin NSAID consumption, whichpoints out some concerns on the current NSAID con-sumption or prescription in Spain.
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Additional files
Additional file 1: NSAID-group ever use by age and sex [%, (95% CI)].(PDF 47 kb)
Additional file 2: NSAID-group current use by age and sex [%, (95% CI)].(PDF 43 kb)
Additional file 3: NSAID ever group use by province of recruitment [%,(95% CI)]. (PDF 21 kb)
Additional file 4: Consumption of specific non-aspirin NSAIDs. Only ac-tive principles with reported anytime-consumption over 1% are included.Data indicate percentage and 95% confidence interval. (PDF 36 kb)
AbbreviationsATC: Therapeutic Classification of Drugs; CEIC: Comité Ético de InvestigaciónClínica; CI: % confidence intervals; FDA: Food and Drug Administration;FFQ: Food Frequency Questionnaire; GI: Gastrointestinal; MCC: Multicase-control; NSAIDs: Non-steroidal anti-inflammatory drugs; OR: Odds ratios
FundingThis work was partially funded by the “Accion Transversal del Cancer”,approved on the Spanish Ministry Council on the 11th October 2007; TheInstituto de Salud Carlos III-FEDER [PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-León, PI09/01903-Valencia, PI09/02078-Huelva,PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810,PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150,PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032]; The FundaciónMarqués de Valdecilla [API 10/09]; The ICGC International Cancer GenomeConsortium CLL (The ICGC CLL-Genome Project is funded by Spanish Minis-terio de Economía y Competitividad (MINECO) through the Instituto de SaludCarlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) delISCIII (RD12/0036/0036)); The Junta de Castilla y León [LE22A10–2]; The Con-sejería de Salud of the Junta de Andalucía [2009-S0143]; The Conselleria deSanitat of the Generalitat Valenciana [AP_061/10]; The Recercaixa [2010ACUP00310]; The Regional Government of the Basque Country; The Consejería deSanidad de la Región de Murcia; The European Commission [grants FOOD-CT-2006-036224-HIWATE]; The Spanish Association Against Cancer (AECC)Scientific Foundation; The Catalan Government DURSI [grant 2014SGR647];The Fundación Caja de Ahorros de Asturias; and the University of Oviedo.The funding body had no role in the design of the study and collection,analysis, and interpretation of data and in writing the manuscript.
Availability of data and materialsThe informed consent obtained from the study participants prevents the fulldata from being made publicly available. The anonymized dataset necessaryto replicate this study’s findings will be available upon request to thecorresponding author.
Authors’ contributionsStudy conception and design: JL and IGA. Statistical analysis: TDS, MP, CPC,JAM, IG-A, JL. Coordination of substudy sites, recruitment, acquisition of data,read and revised the manuscript: GCV, TFV, PA, RC, RP, JMA, VDB, BPG, JE, YB,GFT, ISB, RM, JMH, AT, AB, NA, MP, MK. Drafting of the manuscript: IGA andJL. Contributions to the final version of the manuscript were made by all au-thors. All authors read and approved the final manuscript.
Ethics approval and consent to participateParticipants who agreed to partake in the study signed an informed consentbefore the face-to-face interview, and the protocol of MCC-Spain was ap-proved by the local Ethics Committees of participating institutions (ComitéÉtico de Investigación Clínica (CEIC) del Instituto Municipal de AsistenciaSanitaria de Barcelona; CEIC del Hospital Universitario de Bellvitge; CEIC deNavarra; CEIC del Hospital Universitario La Paz; CEIC del Hospital UniversitarioRamón y Cajal; CEIC de Cantabria; CEIC de Gipuzkoa; CEIC de Granada; CEICde Murcia; CEIC de Valencia; CEIC de Girona; Comité de Ética de la Investiga-ción de la Provincia de Huelva; CEIC de León; Comité Ético de Investigacióndel Principado de Asturias), in conformity to the principles of the Declarationof Helsinki. The database was registered in the Spanish Agency for Data Pro-tection (no. 2102672171).
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details1CIBER Epidemiología y Salud Pública, Madrid, Spain. 2Facultad de Medicina,Universidad de Cantabria – IDIVAL, Avda Herrera Oria s/n, 39011 Santander,Spain. 3Department of Obstetrics and Gynecology, Nuevo Belén UniversityHospital, Madrid, Spain. 4Environmental and Cancer Epidemiology Unit,National Centre for Epidemiology, Carlos III Institute of Health (Instituto deSalud Carlos III–ISCIII), Avda. Monforte de Lemos, 5, 28029 Madrid, Spain.5Institute of Health Research “Puerta de Hierro”, IDIPHIM, Madrid, Spain.6ISGlobal, Centre for Research in Environmental Epidemiology (CREAL),Barcelona, Spain. 7Universitat Pompeu Fabra (UPF), Barcelona, Spain. 8IMIM(Hospital del Mar Medical Research Institute), Barcelona, Spain. 9Institute ofBiomedicine (IBIOMED), University of León, León, Spain. 10Public HealthDivision of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain.11Department of Statistics and O.R., INAMAT, Public University of Navarre,Pamplona, Spain. 12Unit of Infections and Cancer, Cancer EpidemiologyResearch Programme, IDIBELL, Catalan Institute of Oncology, Barcelona,Spain. 13University of Oviedo, Oviedo, Spain. 14Universidad de Granada,Granada, Spain. 15Centro de Investigación en Recursos Naturales, Salud, yMedio Ambiente. (RENSMA), Universidad de Huelva, Huelva, Spain.16Dirección General de Salud Pública, Fundación para el fomento de lainvestigación sanitaria y biomédica de la Comunidad Valenciana,FISABIO-Salud Pública, Valencia, Spain. 17Unitat d’Epidemiologia i Registre deCàncer de Girona (UERCG), Pla Director d’Oncologia, Institut Catalàd’Oncologia, Institut d’Investigaciò Biomèdica de Girona (IdIBGi), Universitatde Girona, Girona, Spain. 18Department of Epidemiology, Murcia RegionalHealth Council, IMIB-Arrixaca, Murcia, Spain. 19Navarra Public Health Institute,Pamplona, Spain. 20Navarra Institute for Health Research (IdiSNA), Pamplona,Spain. 21Osakidetza-Basque Health Service, BioDonostia Research Institute,Donostia, Spain. 22Epidemiology Section, Public Health Division, Departmentof Health of Madrid, Madrid, Spain.
Received: 30 November 2017 Accepted: 4 September 2018
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