2023+实践建议：质子泵抑制剂的心血管兼容性.（英文版）pdf

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1、GUIDELINESCardiovascular Compatibility of Proton PumpInhibitors:Practice RecommendationsJamshed Dalal.Anjan Lal Dutta.Jagdish Hiremath.Shamanna Seshadri Iyengar.Jagadish Chander Mohan.Abraham Ooman.Bhabadev Goswami.Kotacherry Thrivikrama ShenoyReceived:August 24,2023/Accepted:October 18,2023 The Aut

2、hor(s)2023ABSTRACTThis manuscript aims to critically evaluate thecurrent evidence regarding adverse cardiovas-cular effects associated with proton pumpinhibitors(PPIs)in patients with coronaryartery disease(CAD).It also provides guidancefor the selection of the most appropriate PPIwithin the context

3、 of cardiovascular polyphar-macy and emphasizes the importance ofestablishing consensus among clinicians on theneed to prescribe PPIs with limited cytochromeP450(CYP450)enzyme inhibition to reducetherisk of drug interactions.PPIs are among themost widely used drugs for the treatment ofgastroesophage

4、al reux disease(GERD)and theprevention of gastrointestinal(GI)bleeding.The manuscript reports the proceedings fromthe rst practice recommendations meeting onthe cardiovascular compatibility of PPIs in anIndian setting.A panel of eight Indian expertsin cardiology and gastroenterology reviewed 14conse

5、nsus statements.Available literature wassearched and summarized,and after multiplerounds of review,consensus was achieved forthese statements.Based on the available evi-dence,theconsensuspanelhighlightsthataPPIwith minimal drugdrug interaction(DDI)isrecommended,especially in patients requiringclopid

6、ogrel or polypharmacy.Rabeprazoleappears to be a good option in cases where co-prescription is indicated,owing to its optimalacid suppression and minimal drug interactionprole.Keywords:Proton pump inhibitors;Cardio-vascular risk;Polypharmacy;CYP450 enzyme;Clopidogrel;RabeprazoleJ.Dalal(&)Kokilaben D

7、hirubhai Ambani Hospital,Mumbai,Indiae-mail:A.L.DuttaPeerless Hospital&B.K.Roy Research Center,360Panchasayar,Kolkata,IndiaJ.HiremathRuby Hall Hospital,Pune,IndiaS.S.IyengarManipal Hospital,Bangalore,IndiaJ.C.MohanJaipur Golden Hospital,Delhi,IndiaA.OomanApollo Hospital,Chennai,IndiaB.GoswamiDispur

8、Hospital,Guwahati,IndiaK.T.ShenoySree Gokulam Medical College and ResearchFoundation,Trivandrum,IndiaCardiol Therhttps:/doi.org/10.1007/s40119-023-00338-1Key Summary PointsCo-administration of proton pumpinhibitors(PPIs)withdrugsthathavehighafnity for either CYP2C19 or CYP3A4(cytochrome P450 enzyme

9、family)maycause a clinically relevant drugdruginteraction(DDI).Rabeprazole with low afnity for a rangeof CYP isoenzymes or involvement ofadditional elimination processes exhibitsa minor propensity for DDIs compared toother PPIs.The risk of major adverse cardiovascularevents(MACE)was similarly higher

10、 withomeprazole,esomeprazole,lansoprazole,and pantoprazole but not withrabeprazole when given along withclopidogrel.Considering the optimal acid suppressionand minimal drug interaction prole ofrabeprazole,it seems to be a good optionin cases where co-prescription with dualantiplatelet therapy(DAPT)i

11、s indicated.INTRODUCTIONCardiovascular disease(CVD)is the leadingcause of death globally.India accounts for one-fth of the CVD deaths worldwide,especiallyamongyouth.IndiasCVDprevalenceincreasedfrom 25.7 million in 1990 to 54.5 million in2016 1.One study reports that the prevalenceofCVDin1960inurbanI

12、ndiawas2.0%,andby2013ithadincreasedsevenfoldto&14.0%.Therural prevalence more than quadrupled from1.7%in 1970 to 7.4%in 2013 2.Antithrombotic therapy with antiplateletdrugs and oral anticoagulants is the standard ofcare in patients with CVD.Patients undergoingantithrombotic therapy are at risk of ga

13、stroin-testinal(GI)bleeding.Proton pump inhibitors(PPIs)are co-prescribed with antithromboticagentsforgastroprotectionandreducetheriskofGI bleeding.PPIs are potential inhibitors of hep-atic cytochrome P450(CYP450)enzymes,whichmay result in clinically signicant drug interac-tions.Therefore,it is impe

14、rative that effectivestrategiesareusedaswellasregularmonitoringinordertoimprovepatientcompliance3.METHODSA survey was conducted to address several issuesconcerningPPIs.Theobjectiveofthissurveywasto appraise the current evidence on adverse car-diovascular(CV)effectsfromPPIsinpatientswithCVDandprovide

15、guidanceonselectingaPPIwithweakCYP450enzymeinhibition.Aninitiallistof14 statements along with the available literaturewasgeneratedandcirculatedamongtheeightkeyopinion leaders(KOLs)in the eld(six cardiolo-gists/twogastroenterologists).Afterreviewingthestatements,theKOLsvotedonthestatementsbyemail.The

16、optionsgivenforeachstatementwereasfollows:(a)stronglyagree,(b)agreewithsomereservation,and(c)disagree.Consensus on astatement was considered achieved when 80.0%or more of the KOLs chose to strongly agree oragree with some reservation.A statement wasconsidered refuted when 80.0%or more of theKOLschos

17、etodisagree.Thenaldocumentwasagain circulated among the panelists for theirapproval onthe practice recommendations.ThisdocumentprovidesguidancefordoctorsinIndiain choosing a PPI with fewer drugdrug interac-tions(DDI)when prescribing to patients withCVD,thereby reducing the risk of adverse CVeffectsa

18、nddruginteractions.Thisarticledoesnotcontainanynewstudieswithhumanparticipantsoranimalsperformedbyanyoftheauthors.PRACTICE RECOMMENDATIONSTATEMENTSStatement 1:There Is a Strong AssociationBetween Cardiac and GI DisordersReview of the LiteratureThere is a clear link between heart disease andGI proble

19、ms(Fig.1).Most patients attributeCardiol Thertheir coronary artery disease(CAD)symptomsto gas and acidity,which results in delayeddiagnosis and poor outcomes of CAD.Gastroesophageal reux disease(GERD)isassociated not only with non-cardiac chest painepisodes,but also with increased incidence ofischem

20、ic events in patients with CVD andrefractory chest pain 4.In patients with CADundergoing percutaneous coronary interven-tion(PCI),antithrombotic therapy is used tominimize the risk of stent thrombosis andrecurrent CV events 5.Antithrombotic ther-apy is associated with high risk of GI bleeding.Increa

21、sed GI bleeding is associated with anincreased risk of CV events and mortality,andprolonged hospitalization 6.Polypharmacywith drugs used to manage CVD can causeupper GI symptoms.Some drugs used to treatupper GI symptoms may increase CVD riskeither directly or through drugdrug interac-tions.Therefor

22、e,recognizing patients with bothCVD and upper GI conditions is an importantstepintheclinicalcaresetting7.PPIuseforanextended period of time may suppressdimethylarginine dimethylaminohydrolase(DDAH)activity.This leads to increased asym-metrical dimethyl arginine(ADMA)levelswhich inhibit nitric oxide(

23、NO)synthesis andincrease the risk of CVD 8.Statement 2:Increased GI BleedingIncreases CV Events,Mortality,and Prolonged HospitalizationReview of the LiteratureAcute myocardial infarction(AMI),percuta-neous coronary intervention(PCI),and antico-agulant or antiplatelet drugs are all known tocause GI b

24、leeding in patients admitted to thecardiology department 9.Not only does thiscause prolonged hospitalization but alsoincreases the risk of CV events and mortality(Fig.2)10.Post-procedural bleeding episodeswere linked to an elevated risk of in-hospitalmortalityinalargeregistryofPCIpatients,withan est

25、imated 12.1%of fatalities due to bleedingcomplications11.GIbleedingisacatastrophiccondition in the setting of acute coronary syn-drome(ACS).It is associated with increasedrates of mortality,nonfatal MI,stent thrombo-sis,andprolongedhospitalization.Thedurationof hospitalization is twice as long in pa

26、tientswith GI bleeding as in those without GI bleed-ing 12.GI bleeding adversely affects CADoutcomes in many ways.One of them which isnot often discussed is that secondary to bleed-ing as a compensatory mechanism,coagulationfactors become more proactive resulting inmore thrombotic events 6.According

27、 toFig.1 Association between cardiac and GI disorders.Thisgure illustrates the strong association between cardiac andGI disorders.The consensus level among participants was100%,with 62%strongly agreeing and 38%agreeing withsome reservations.GI gastrointestinalFig.2 Consequences ofincreasedGI bleedin

28、g with respectto cardiovascular events,mortality,and hospitalization.The gure illustrates the association between increased GIbleeding and its consequences,including cardiovascularevents,mortality,and prolonged hospitalization.Theconsensus level reached 100%agreement.GIgastrointestinalCardiol Therin

29、ternationalsocietalguidelines,patientswithahistory of upper GI bleeding should take PPIs tominimize GI bleeding.PPIs are helpful forpatients who require antiplatelet medicationand have associated risk factors for GI bleeding13.Statement 3:There Is an Immense Burdenof Polypharmacy and Signicant DDIin

30、 Cardiac PatientsReview of LiteraturePatients with CVD need to be prescribed two ormore essential drugs 14.These drugs togethercan cause drug interactions(Fig.3).Cardiovas-cular pharmaceuticals make up 48.0%of allprescribed medications,which is quite high15.A study which included 466 patientsshowed

31、that 26.7%of participants met the cri-teria of polypharmacy.Polypharmacy,whilesometimes unavoidable,is not always effectiveor safe.It can have a high risk of negative sideeffects 16.The most severe medication inter-actions were identied to be aspirin?clopido-grel(46.8%)and omeprazole?clopidogrel(32.

32、4%)in the same prescription.It has beenshownthatcombiningaPPIwithclopidogrelina single prescription can result in serious med-ication interactions 15.Despite these interac-tions,PPIs have been suggested as a way toreduce the risk of GI bleeding after dual anti-platelet therapy(DAPT).The patients GI

33、riskmust be assessed,and PPIs with the least inter-action with clopidogrel must be chosen care-fully 15.Therefore,clinicians shoulddifferentiate between appropriate and inappro-priate polypharmacy and strive to reduce inap-propriate polypharmacy and severe DDI 16.Statement 4:The Most Prescribed Sing

34、leDrug in Cardiac Patients Is Aspirinand the Fixed-Dose Combination IsAspirin1 ClopidogrelReview of the LiteratureAntiplatelet agents(67.7%)dominate the car-diology outpatient department(OPD)prescrib-ing trend and are projected to overtake anti-cholesterol medications as the top seller.Themost presc

35、ribed single drug was aspirin(59.9%)17(Fig.4).Aspirin and clopidogrel were themost widely recommended antiplatelet drugsfor the treatment of CVD 18.The combination of aspirin and clopidogrelis essential in the treatment of CVD becausethedrugs minimize the risk of additional clot for-mation and help

36、to improve survival rates 18.Platelet activation is inhibited by aspirin andclopidogrel through complementary but dis-tinct mechanisms.Both these antiplatelet drugshave a substantial protective impact againstunfavorable vascular events,but the combina-tion of the two agents has an even strongerantip

37、latelet effect,resulting in superiorantithrombotic protection in CVD and periph-eral arterial disease(PAD)19.Statement 5:PPIs Are Recommendedfor Gastroprotection in Patients with CADReceiving Antithrombotic TherapyReview of the LiteratureDAPT with aspirin and a P2Y12 inhibitorimproves CV outcomes in

38、 patients with acutecoronary syndrome(ACS)and is recommendedby guidelines for one year following initialhospitalization 20.Clopidogrel has beenlinked to an elevated risk of upper GI bleedingandulcers.ToreducetheriskofGIhemorrhage,PPIs are recommended.In CAD,PPIs have beendemonstrated to minimize dys

39、pepsia caused byFig.3 Polypharmacy and DDI burden in cardiac patients.The gure highlights a signicant consensus level(100%)regarding the burden of polypharmacy and DDI in cardiacpatients,with 62%strongly agreeing and 38%agreeingwith some reservations.DDI drugdrug interactionCardiol TherDAPT and to a

40、chieve a clinically signicantreduction in GI bleeding 20.According to asystematic assessment of 18 randomized con-trolled trials(RCTs)involving over 10,000patients,PPIs reduced peptic ulcer bleeding byalmost 80.0%when compared to controls 21.Mistry et al.reported that gastroprotection inthe form of

41、PPIs is required for patients onDAPT and/or with a history of GI bleeding 22.A meta-analysis conducted by Almueh et al.reported that PPIs are superior to H2 receptorantagonists(H2RAs)for gastroprotection inpatients on DAPT 23.These data suggest thatPPI therapy has a denite gastroprotective roleinpat

42、ientswithCVD(Fig.5)whoareprescribedantiplatelets,but the usage should be in accor-dance with the recommended dose and treat-ment period 24.Statement 6:PPIs Affect the Efcacyof DAPT in Cardiac PatientsReview of the LiteratureClopidogrel has been used as an antiplateletdrug in most studies for DAPT.Co

43、ncurrent useof clopidogrel and PPIs may reduce the overallefcacy of clopidogrel(Fig.6)due to the DDIsbetween some PPIs and clopidogrel,metabo-lizedviathesameCYP450liverenzymes25.In2009,the Food and Drug Administration(FDA)issued a warning about concomitant use ofclopidogrel and certain PPIs,as the a

44、ntiplateletactionofclopidogrelmaybelimitedbyPPIslikeomeprazole and esomeprazole 26.Yamaneet al.reported that omeprazole lowered clopi-dogrels antiplatelet action more than rabepra-zole 26.Among individual PPIs,onlyomeprazole was signicantly linked with anincreased risk of hospitalization for ACS 27.

45、The results of a meta-analysis exploring the riskof major adverse cardiovascular events(MACE)following combined use of clopidogrel and PPIsin patientswith CAD showed thatthe increasedrisk of MACE was similarly high with omepra-zole,esomeprazole,lansoprazole,and panto-prazole but not with rabeprazole

46、 28.A studyby Parri et al.showed that pantoprazoleincreased the adenosine diphosphate-inducedmaximal aggregation(ADP-MA)in patientswith ST-elevation myocardial infarction(STEMI)treated with DAPT.It signicantlyinterferes with the antiplatelet effects of clopi-dogrel.Therefore,pantoprazole is not a sa

47、ferchoice for patients on DAPT 29.The availableevidence suggests that there is an increased riskof MACE in patients with concomitant use ofclopidogrel and PPIs,but it is different for dif-ferent PPIs 30.In the last few years,newerantiplatelet agents(ticagrelor/prasugrel)havebeen used as alternatives

48、 to clopidogrel aftercoronary intervention.There are no knowndrug interactions with prasugrel and ticagrelorFig.4 Aspirin and aspirin?clopidogrelcommon med-ications in cardiac patients.The gure summarizes thecommon medications used in cardiac patient care,includ-ing aspirin as the single drug and th

49、e combination ofaspirin?clopidogrel.The consensus level was 100%,with87%strongly agreeing and 13%agreeing with somereservationsFig.5 PPI recommendations for gastroprotection inpatients with CAD.The gure highlights the recommen-dations for PPIs in providing gastroprotection for patientswith CAD,with

50、a consensus level of 100%,including 87%strongly agreeing and 13%agreeing with some reservations.CAD coronary artery disease,PPI proton pump inhibitorCardiol Therthat would signicantly hinder their antiplate-let effects 31.Statement 7:PPIs and Antiplatelet DrugsShare a Common Cytochrome P450Metabolic