Proton pump inhibitors and the risk of severe adverse events : a cardiovascular bombshell?

Re Po Ca diol. 2018;37(10):859---863 www. e po ca diol.o g Re is a Po uguesa de Ca diologia Po uguese Jou nal o Ca diology REVIEW ARTICLE P o on pump inhibi o s and he isk o se e e ad e se e en s --- A ca dio ascula bombshell?夽 Nelson Cunhaa,∗, An ónio Ped o Machadob aSe ic¸o de Ca diologia, Hospi al Uni e si á io de San a Ma ia (CHLN), Cen o Académico de Medicina de Lisboa e CCUL, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, Po ugal bSe ic¸o de Medicina I B, CHLN - Hospi al de San a Ma ia, Lisboa, Po ugal Recei ed 20 Sep embe 2017; accep ed 8 Oc obe 2017 KEYWORDS P o on pump inhibi o s; Ni ic oxide; Acu e co ona y synd ome; S oke Abs ac P o on pump inhibi o s a e cu en ly one o he mos p esc ibed pha macological classes in de eloped coun ies, gi en hei e ec i eness and sa e y p o ile, which has un il now been conside ed a o able. Howe e , in ecen yea s, se e al pape s ha e been published ha associa e p olonged use o hese d ugs wi h a wide ange o ad e se e ec s, posing doub s abou hei sa e y. Among he ad e se e ec s desc ibed is an inc eased isk o ca dio ascula e en s. This ela ionship was i s desc ibed in subjec s a e acu e co ona y synd ome due o he in e e ence o p o on pump inhibi o s in he cy och ome P450 2C19 and he con e sion o clopidog el o i s ac i e me aboli e. Mo e ecen s udies ha e also epo ed his ela ionship wi h he use o an ipla ele agen s ha do no depend on cy och ome P450 2C19 ac i a ion. The p oposed mechanism is inhibi ion o dime hyla ginine dime hylaminohyd olase, a physiological inhibi o o asymme ic dime hyla ginine, which inc eases plasma concen a ions o he la e enzyme, leading o lowe le els o ni ic oxide. By e iewing in his a icle he ela ionship be ween he use o p o on pump inhibi o s and inc eased isk o ca dio ascula and ce eb o ascula e en s, he au ho s aim o ale he medical communi y o he po en ially ha m ul e ec s o hese d ugs, and ecommend he se ing o a mo a o ium on hei p olonged use. © 2018 Sociedade Po uguesa de Ca diologia. Published by Else ie Espa˜ na, S.L.U. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by- nc-nd/4.0/). 夽Please ci e his a icle as: Cunha N, Machado AP. Inibido es da bomba de p o ões e o isco de e en os ad e sos g a es --- uma bomba ca dio ascula ?. Re Po Ca diol. 2018;37:859---863. ∗Co esponding au ho . E-mail add ess: [email p o ec ed] (N. Cunha). 2174-2049/© 2018 Sociedade Po uguesa de Ca diologia. Published by Else ie Espa˜ na, S.L.U. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). 860 N. Cunha, A.P. Machado PALAVRAS-CHAVE Inibido es da bomba de p o ões; Óxido ní ico; Sínd ome co oná ia aguda; Aciden e ascula ce eb al Inibido es da bomba de p o ões e o isco de e en os ad e sos g a es --- uma bomba ca dio ascula ? Resumo Os inibido es da bomba de p o ões são a ualmen e uma das classes a macológicas mais p esc i as nos países desen ol idos, dada a sua e icácia e pe il de segu anc¸a a é en ão conside ado a o á el. Con udo ao longo dos úl imos anos, êm sido publicados á ios abalhos que associam o uso p olongado des es á macos a uma panóplia de e ei os ad e sos, colocando dú idas ace ca da sua segu anc¸a. En e os e ei os ad e sos desc i os, salien a-se o aumen o do isco de e en os ca dio ascula es. Es a elac¸ão oi p imei amen e desc i a nos indi íduos após sín- d ome co oná ia aguda pela in e e ência dos inibido es da bomba de p o ões no ci oc omo P450 2C19 e a con e são do clopidog el em me aboli o a i o. No en an o, abalhos mais ecen es desc e em es a elac¸ão ambém com o uso de an iag egan es que não dependem da a i ac¸ão pelo ci oc omo P450 2C19. O mecanismo p opos o é pela inibic¸ão da dime ila ginina dime ilaminohid olase, inibido isiológico da dime ila ginina assimé ica, aumen ando assim as concen ac¸ões plasmá icas des a úl ima enzima e po sua ez aduzindo-se em ní eis mais eduzidos de óxido ní ico. Os au o es ao e e nes e a igo a elac¸ão en e o uso de inibido es da bomba de p o ões e o isco ac escido de e en os ca dio e ce eb o ascula es, p e endem ale a a comunidade cien í ica pa a os po enciais e ei os ne as os des es á macos e ecomendam a colocac¸ão de uma mo a ó ia à sua u ilizac¸ão p olongada. © 2018 Sociedade Po uguesa de Ca diologia. Publicado po Else ie Espa˜ na, S.L.U. Es e ´ e um a igo Open Access sob uma licenc¸a CC BY-NC-ND (h p://c ea i ecommons.o g/licenses/by- nc-nd/4.0/). In oduc ion P o on pump inhibi o s (PPIs) we e he six h mos p esc ibed pha macological class in Po ugal in 2015, wi h 6.99 million uni s sold, and he eigh h in alue (41.2 million eu os a wholesale p ices), acco ding o da a om S a is ics Po u- gal, he na ional s a is ics ins i u e. Fac o s con ibu ing o his high consump ion include hese d ugs’ e icacy in ea ing dyspepsia, pep ic ulce , gas oesophageal e lux disease and e osi e esophagi is, a sa e y p o ile ha has been conside ed a o able, he all in p ices as gene ic e sions en e ed he ma ke , inap- p op ia e p esc ibing and use o pe iods exceeding hose ecommended, and ebound acid hype sec e ion.1 --- 3 The ebound e ec , in which dyspepsia ecu s a e wi hd awal o ea men , and which leads o dependence, is one o he main easons o ch onic use o PPIs in a la ge and g owing numbe o pa ien s. Pa adoxically, he d ugs induce he symp oms hey a e supposed o ea .4 The de elopmen o dependence may explain he esul s o a s udy in he UK showing ha he o al olume o PPIs p esc ibed ose en old in ou yea s, wi h epea p e- sc ip ions accoun ing o 77% o he o al in he las yea analyzed.5In a US s udy, PPIs we e p esc ibed app op ia ely in only 35% o cases; hey we e p esc ibed o gas op o ec- ion in 18% and in 36% he e was no documen ed app op ia e indica ion.6 PPIs cause hype gas inemia and achlo hyd ia. In he sho e m, hype gas inemia leads o hype acidi y, wo sen- ing he symp oms o gas oesophageal e lux and dyspepsia, when ea men is wi hd awn.3,7 In he long e m, i can esul in en e och oma in-like cell hype plasia and pa ie al cell hype ophy, leading o dyspepsia and inc easing he isk o ca cinoid umo s.8 Despi e he widely held a o able opinion o he sa e y o PPIs, esul s published in ecen yea s ha e aised se ious ques ions conce ning hei p olonged use. A g owing numbe o s udies and edi o ials ha e begun o call a en ion o he associa ion be ween PPI use and inc eased isk o a a ie y o condi ions. These include Clos idium di icile-associa ed dia hea and en e ic in ec ion wi h Campylobac e , Salmonella, Shigella and Lis e ia9---11; communi y-acqui ed pneumonia12---14; bone ac u es, pa icula ly wi h e y long ea men pe iods15---17; dose-dependen inc eases in ex ahepa ic cholangioca ci- noma and ca cinoma o he ampulla o Va e , duodenum, jejunum and panc eas18---20; esophageal adenoca cinoma in indi iduals wi h Ba e ’s esophagus21; acu e in e s i ial neph i is22 and ch onic kidney disease23; and a he o h om- bo ic ca dio ascula e en s.24,25 P o on pump inhibi o s and isk o ca dio ascula e en s The i s epo s o an inc eased isk o ca dio ascula e en s associa ed wi h PPIs came om s udies on pa ien s wi h a his o y o acu e co ona y synd ome ea ed wi h clopido- g el. These s udies ini ially a ibu ed his ise in a es o ein a c ion and o he acu e co ona y e en s a e hospi- al discha ge o he educ ion in clopidog el’s an ipla ele e ec caused by he PPI in e e ing in i s con e sion in he P o on pump inhibi o s and he isk o se e e ad e se e en s --- A ca dio ascula bombshell?夽861 li e o he ac i e me aboli e by blocking he cy och ome P450 2C19 (CYP2C19).26,27 In iew o he con o e sy su ounding hese ea ly s ud- ies, a sys ema ic e iew and me a-analysis28 was pe o med examining only s udies published be ween 2012 and 2016. This con i med ha he concomi an use o clopidog el and PPIs ollowing co ona y angioplas y was associa ed wi h highe sho - e m mo ali y and a highe long- e m incidence o majo ad e se ca diac e en s, myoca dial in a c ion and s en h ombosis, al hough long- e m mo - ali y was no signi ican ly di e en . Howe e , o he ecen s udies ha e associa ed PPIs no only wi h wo se clinical ou comes when used concomi an ly wi h clopidog el in high ca dio ascula isk popula ions, bu also wi h educed he apeu ic bene i o o he an ipla ele agen s, such as aspi in and icag elo , which do no in ol e ac i a ion o he CYP2C19 isoenzyme, sugges ing ha ano he mechanism is a wo k.29---31 This appea s o be co - obo a ed by o he s udies showing ha all membe s o he PPI pha macological class, e en hose wi h a minimal e ec on CYP2C19, inc ease ca dio ascula isk in pa ien s wi h acu e co ona y synd ome.24,26,30,32---34 Va ious g oups ha e sugges ed ha his inc eased isk is mainly due o educed endo helial p oduc ion o ni ic oxide (NO), which unc ions as an endogenous pla ele inhibi o . Thus, he e ec o PPIs on pla ele agg ega ion would esul om hei dele e ious e ec on endo helial unc ion.35 NO eleased by endo helial cells plays a c ucial ole in ascula homeos asis, ac ing as an endogenous asodila- o egula ing local ascula one, as an endogenous pla ele inhibi o egula ing pla ele ac i i y, and h ough i s an ia he ogenic ac ion on he endo helium, main aining he no mal s uc u e o he essel wall.36 NO syn hesis in essels is egula ed by endo helial NO syn hase,37 which is inhibi ed by ADMA (asymme ic dime hyla ginine), such ha highe le els o ADMA educe endo helial NO p oduc ion.38 Plasma ADMA concen a ions a e ele a ed in enal ailu e, co ona y disease, hype ension, diabe es and p e- eclampsia. When pa ien s wi h hese condi ions ake PPIs, ADMA le els in endo helial cells ise e en mo e, u he inhibi ing NO syn hase, educing endo helial NO p oduc ion and exace ba ing endo helial dys unc ion. As he bioa ail- abili y o NO diminishes, condi ions a o he p og ession o a he oscle osis and he occu ence o a he o h ombo ic e en s.25,39 PPIs inc ease plasma ADMA le els and educe endo helial NO p oduc ion by inhibi ing dime hyla ginine dime hy- laminohyd olase (DDAH), an enzyme ha deg ades ADMA.40 The esea ch g oup ha iden i ied his cascade epo ed ha in he same p eclinical s udy ADMA le els ose by a ound 30% in ex- i o human endo helial cells exposed o a PPI and in- i o se um concen a ions ose by abou 20% in mice ecei ing a PPI.40 The same g oup ecen ly pe o med a p ospec i e c osso e pilo s udy in 21 indi iduals (11 heal hy and 10 wi h es ablished ca dio ascula disease) o assess in i o he co ela ion in humans be ween PPI use and ADMA le els and endo helial unc ion. Al hough PPI use did no signi i- can ly in luence ascula endo helial unc ion, highe ADMA le els we e obse ed in he PPI a m, and his end was mo e p onounced among subjec s wi h a his o y o ascula disease.41 Howe e , his s udy has some me hodological laws, pa - icula ly he sho ea men pe iod ( ou weeks in each g oup) and he small sample size, which would be unlikely o p o ide esul s wi h s a is ical signi icance. Fu he mo e, he EndoPAT echnique used in he s udy o assess he e ec o d ugs on ascula unc ion is no he ideal es o de ec a ia ions in endo helial unc ion in he ea ly s ages o clinical d ug ials,42 and he al e a ions iden i ied by his me hod may be pa ly NO-dependen .43 The s udy has o he limi a ions ha a e beyond he scope o his e iew. E en so, since he e is a endency o highe ADMA le els wi h PPI use, he e appea s o be a need o s udies wi h mo e ep esen a i e popula ions and longe ollow-up, in o de o ob ain esul s wi h clinical signi icance. As s a ed abo e, i is known ha ele a ed plasma ADMA le els a e a isk ac o o ca dio ascula mo bidi y and mo ali y, in bo h pa ien s wi h ca dio ascula disease and appa en ly heal hy indi iduals.44---50 The la e associa ion is hus a po en ially se ious public heal h p oblem ha should be in es iga ed. On he assump ion ha PPIs can inc ease le els o ADMA e en in heal hy indi iduals, i is essen ial o assess he ela- ionship be ween PPI use and he isk o a i s ca dio ascula e en in he popula ion wi hou known ca dio ascula dis- ease. The olume o s udies published on his subjec has inc eased ma kedly in ecen yea s. Examining he associ- a ion be ween PPI mono he apy and ca dio ascula e en s in indi iduals wi h no his o y o ca dio ascula disease, Sun e al.51 pe o med a me a-analysis o 16 andomized con olled ials including 7540 indi iduals on PPI mono he - apy o gas oesophageal e lux disease. The esul s show a 70% inc eased ca dio ascula isk in pa ien s aking PPIs ( ela i e isk 1.70, 95% con idence in e al [CI] 1.13- 2.56, p=0.01, I2=0%), an associa ion ha appea ed o be s onge in he omep azole and long- e m ea men sub- g oups. The e ha e been ew s udies on he associa ion be ween PPI use and ca dio ascula e en s ha included s oke in he combined endpoin s24,30,31,52---55 and only one assessed ecu - en s oke as i s p ima y endpoin . Wang e al. acco dingly pe o med a e ospec i e analysis based on a na ionwide da abase o assess he ela ion be ween isk o a i s ischemic ce eb o ascula e en and PPI use in he Taiwanese popula ion. They compa ed hospi aliza ions wi h a p ima y diagnosis o ischemic s oke in indi iduals wi h and wi h- ou cu en PPI use a a 1:1 a io. PPI use was associa ed wi h a highe isk o a i s ischemic s oke, independen ly o an ipla ele he apy, wi h a haza d a io o 1.36 (95% CI 1.14- 1.620, p=0.001). The associa ion was s onge in pa ien s aged <60 yea s.56 Conclusion On he basis o he esul s o he abo e s udies, which sugges a causal ela ion be ween PPI use and inc eased isk o ca dio ascula e en s, en e ic in ec ions, pneumo- nia, ch onic kidney disease and cance , among o he s, he 862 N. Cunha, A.P. Machado au ho s ecommend a leas he se ing o a mo a o ium on hei p olonged use. Wide awa eness o hese wo ying da a on he sa e y o long- e m PPI use should p omp discussion o hei use (and abuse) in Po ugal, and help b ing abou mo e a ional p esc ibing o hese d ugs. Con lic s o in e es The au ho s ha e no con lic s o in e es o decla e. Re e ences 1. Ribei o S, Ba hy J, T abulo D, e al. Uso inap op iado de inibido es da bomba de p o ões num se ic¸o de medicina in e na. J Po Gas en e ol. 2014;21:9---14. 2. Niklasson A, Linds öm L, Sim én M, e al. Dyspep ic symp om de elopmen a e discon inua ion o a p o on pump inhibi o : a double-blind placebo-con olled ial. 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