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Data may be preliminary. naEngell Anna statins: review and systematic antagonists A K vitamin between interactions Drug-drug sas novdi h eaoimo h aoiyo ttn.6 odiitaino K n ttn is statins and VKA of Coadministration Denmark.[7] statins.[6] in of statins taking majority (OATP1B1), users the warfarin 1B1 of of polypeptide 50% metabolism approximately transporting the with anion in common organic involved also protein; also statins rosuvastatin).[6] of and transport is (fluvastatin metabolism membrane The CYP2C9 worldwide.[5] and the users lovastatin) Furthermore, fre- statin and most million atorvastatin, (simvastatin, the 200 of CYP3A4 than involves one more comprises with treatments, (statins) drug inhibitors most quent reductase the 4] HMG-CoA CYP2C19.[2, with being while and treatment CYP2C9 CYP2C9 Cholesterol-lowering CYP2C9 by with both metabolized are respectively, by primarily CYP3A4 metabolized R-warfarin, is and is Phenprocoumon commonly and CYP2C9 acenocoumarol warfarin.[2-4] also S-warfarin enzymes for are pathway P450 of metabolic phenprocoumon cytochrome metabolism important and The the substantial countries.[4] acenocoumarol for European but and responsible some VKA, index in fever).[3] prescribed as therapeutic especially (e.g. widely well narrow used, factors most as a other the thromboses and to is variation, avoid influenced Warfarin due genetic be to can challenging, food, VKA range certain Time of be interactions, therapeutic effect Prothrombin can anticoagulant drug-drug the the the by VKA Furthermore, or within dose-response.[1] measurement of (INR) levels in by ratio variation use INR interindividual monitored normalized The achieve international is to 2] the effect essential tests; bleedings.[1, anticoagulant is blood The two It X. following events. and (PTT). the thromboembolic VII of dependent of II, one K prevention of factor vitamin and the including with treatment factors interfering long-term by coagulation in effect anticoagulant used their are exhibit of They (VKA) be antagonists to K likely Vitamin is effect The statin 0.15-0.65. following from Introduction VKA ranged of INR effect most individually. mean anticoagulant evaluated the in the was be simvastatin increases should in final while but reported increase the warfarin relevance The In minor was clinical a obtained. studies limited treatment. strategies showed were the VKA search hits studies in unique during broad VKA included 8,623 two used initiation All Pubmed, PRISMA frequent Applying and statin. most the Embase users. The initiated to both VKA commonly according included. in among were review statins coagulation studies and systematic eight on VKA a sample between initiation performed interaction statin we drug of the Therefore, clinical effect for However, the divergent. patients. cardiovascular evaluate are in to frequent combination guidelines is drug statins this and (VKA) on antagonists guidelines K Vitamin of use Concomitant Abstract Abstract 2020 10, September 4 3 2 1 Pottegard Anton ydnkUiesttDtSnhdvdnkblg Fakultet Sundhedsvidenskabelige Det Universitet Syddansk Denmark Southern of University Hospital University Odense Hospital Hvidovre 1 nra Svendsen Andreas , 3 2 etSre Lind Struer Bent , 1 1 oeStage Tore , 3 aaHellfritzsch Maja , γ- abxlto fblood of carboxylation 4 and , Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. a u otesuisntcnenn el ntae ttntetet( 9.Afl vriwo the of overview full A 29). = (n treatment statin in in initiated found newly entries studies be concerning eight not can these, corresponding Of studies studies screening. the included full-text to to for due studies 80 hyperlinked was ( selected and included abstracts are were and titles 8,623 article screened We this in Results PHAR- ligands to Guide IUPHAR/BPS the and from a MACOLOGY. data for on targets portal based common the http://www.guidetopharmacology.org, AOS) protein and group. (AEE Key author reviewers entire Ligands two the and by the Targets analyzed of by and Nomenclature interpreted publications, and included form collection the data from pre-defined extracted were Data meet- criteria. publications clinical inclusion original abovementioned additional the for the publications or ing original adjustments, included all dose were cross-reference-searched volunteers we VKA Lastly, healthy outcome statin concerning an PTT, the publications report INR, and ii) should reviews in humans, reports, studies changes from Case excluded. the data including thrombosis. iii) judged presented or coagulation, as and bleeding studies above, treatment; of outcomes the mentioned VKA degree as i) stable to criteria that during inclusion related required initiated same we be the Furthermore, should meet treatment to the read. studies text via should required full statins. judged title we by and as the round, VKA available, second statins, of was the use and abstract In concomitant no VKA concerned if evaluating of study Lastly, data the use discrepancies original proceedings. that concomitant and reported conference indicate they AOS), excluded with if we were and associated Further, inclusion articles (AEE initial interaction abstract. round, reviewers for drug-drug first two eligible the were possible by In Studies a independently consensus. rounds. abstracts two via and solved into were titles divided were their process by selection screened and review platform EMBASE software subsequent and web-based The PubMed the extraction to in data imported searches and selection were two Study articles The All X. respectively. Appendix hits, in 8,450 detail Covidence. and in 878 PubMed described in in are resulted search text searches and sepa- free specific two drug with The performed combined more We terms 2020. the MESH June Embase. in and to keywords in ‘English inception relevant (Medline) and and from using Pubmed ‘human’ searched searches were Limits literature included databases rate con- Ovid). The used AOS) Elsevier; applied. databases and Medica, were (Exerpta (AEE language’ The Embase doctors database medical oriented search. two pharmacological literature review,[11,12] systematic the for of ducted guidelines effect PRISMA anticoagulant the the literature Following on systematic initiation a statin conducted of Methods we effect the statins, on and evidence VKA available relevance VKAs. collectively between clinical the the interactions assess of when To drug-drug monitoring review changes.[8-10] INR potential dose of following the frequency increased recommended and the is of treatment with increase it statin to associated Nevertheless, discontinuing databases potentially or relevance. interaction clinical initiating increases drug-drug limited online INR of used changes moderate commonly have INR by to Studies small data leads as conflicting. pathways, well and initiation metabolic effects limited statin anticoagulant overlapping are the that groups drug and reported two VKA the both and between interactions statins drug-drug of potential use about concomitant widespread the Despite iue1 Figure .Tems omnrao o xldn tde uigfl-etscreening full-text during studies excluding for reason common most The ). al 1 Table u fteegticue tde,fu tde investigated studies four studies, included eight the of Out . 2 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. 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Data may be preliminary. ihntefis i ek fe ntaino ttntetet n eue utemr ih00 mg/day 0.07 with furthermore users reduced acenocoumarol and in treatment, mg/day statin 0.04 of VKA and initiation acenocoumarol. users after for phenprocoumon observed weeks was in six effect mg/day first no INR 0.02 the while sim- on with within users, statins effect decreased the phenprocoumon immediate with among the was phenprocoumon treatment 0.1 statins, in dose phen- initiated of all patients respectively, with For increase 435 303), treated an fluvastatin. = in was patients or (n rosuvastatin The INR (6- pravastatin, acenocoumarol studied.[17] on long-term atorvastatin, and were and statins vastatin, 435) treatment treatment) of = acenocoumarol statin effects (n in of treatment) procoumon exposed patients initiation statin 303 after the of week and of treatment initiation 1 evaluation size average after the coagulation. the (on weeks to of were immediate relevance 12 level the neither lesser on study, groups.[20] have treatment and another three to statin stated, In of considered other was initiation was the statins of study between groups effect included this in the therefore four the group of users, of The residual warfarin INR type INR. of the decreased the and population in in increased of were experienced change specification 7.1% patients the and No 17.3% 7.8% to and while (67.9%), respectively, according group levels, nonevent groups the initiation four in to were in patients related INR categorized (2.0 in nonevents were INR changes compromised: any with treatment, find patients statin not when of did treatment, interactions as warfarin.[18] drug pravastatin, with statin 1.07- interact warfarin-associated drug; CI to of of reference expected (95% chosen study not 1.39 was increased the pilot therefore of No with A and OR treatment enzymes estimates. CYP not an initiating reliable by obtain when with had metabolized atorvastatin to observed, treatment not but for cases was is 31-60 initiating pravastatin and few case, bleeding highest after 1.07-2.39), too GI was the days CI were of bleeding 1-30 as there (95% risk GI treatment, highest 1.60 statin of fluvastatin was of with of Concerning risk bleeding (OR) matched the type 1.81). GI Ratio was users, same Odds of bleeding warfarin an risk the chronic GI with the In with with initiation treatment simvastatin case bleedings. after patient initiated GI days 277), Each to had = due whom 113). (n hospitalized simvastatin = controls, been 16), (n 50 = pravastatin (n to and fluvastatin up bleeding.[13] 499) with (GI) treatment = gastrointestinal initiating to (n in of due patients atorvastatin or days/weeks hospitalization warfarin initiation fibrates of included of statin of risk following initiation study the number whether increased dose The the assessed users warfarin study warfarin about daily case-control chronic observational in the information An statins of the 14] no respectively.[13, reduction from with 9%, mean obtained and subsequent a initiated, 7% were the reported from values been studies and INR had treatment Two simvastatin baseline the simvastatin between.[14] initiating at study, after to 2.50 this from prior visit INR In clinic clinic mean anticoagulation treatment.[14] in the simvastatin increase to of an visit reported patient’s initiation (n=29) after study it smaller 3.15 Furthermore, A treatment.[19] to 2.40 0.29).[19] simvastatin vs from of 0.33 INR initiation of mean ( (increase after in high-dose weeks Similarly, increase that treatment.[13] increase four an simvastatin a shown approximately an found of was reported found patients peaking initiation after 1,363 users, also all weeks including warfarin 2.71 warfarin, four study 5,637 to 2.58, with cohort from to register-based medical treated data baseline large at including patients known another study, 2.43 in any from largest INR initiation The to mean simvastatin INR. due in mean on not in focused increase and that small trial, studies the three to The stable due in patients only comprising treatment trials, including 16] treatment drug statin warfarin, condition.[15, statin controlled with receiving initiating prospective interactions studies were of treatment eight drug studies effect all warfarin included several the Although the addressed on population.[20] of study specifically study Two one the statins.[20] six focused while of in studies activity,[13-19] size patients seven coagulation the 5,637 only on report to criteria, not 7 inclusion from did our ranged study one met population statin phenprocoumon while included in which studies, the patients specify the of concerned of size not included study The did studies treatment.[17] one seven study acenocoumarol whereas VKA-treatment, only,[13-16],[18-20] one and the treatment Finally, Concerning warfarin type.[17-19] with.[20] studies in treatment statin three patients initiating one while > 0m)adlwds ivsai ( simvastatin low-dose and mg) 40 < INR < .) nraig(N[].) eraig(N[].)adrsda.Most residual. and (INR[?]1.5) decreasing (INR[?]4.0), increasing 3.0), > . and 1.8 3 < . ntepro f6 aspirt initiation to prior days 60 of period the in 3.2 < 0m)ldt oprbecagsi INR in changes comparable to led mg) 40 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. nweg nteeet fsai ramn ntaigo nioglto nsal K ramn slim- is treatment VKA stable in anticoagulation on initiating treatment statin VKA. of with effects treated the patients on Knowledge among [23, INR statins on hypothesis. of this initiation initiation support Conclusion statin after to cholesterol An weeks of required antifungals.[22] in four impact is azole changes data for about of maximum further seen effect stabilize the However, the levels e.g. with to as Cholesterol coinciding related increase, INR 24] be metabolism. of could warfarin onset associations on faster observed levels a the on to for statins inhibition, lead explanation several P450 to alternative cytochrome of pharmacological expected through effect mediated the be unspecific considering be would enhance the However, not and which might to weeks) interaction metabolism.[14] potential drug-drug (˜four CYP-dependent this interaction the effectiveness, drug-drug its have warfarin knowledge the statins inhibiting in our delay that competitively to substantial suggests is by the statins data warfarin and vitro of studies, VKA In activity the between of interaction described. heterogeneity potential fully the the not to of feasible. Due mechanism INR.[21] considered pharmacological explain in not might The increases was information observed meta-analysis laboratory characteriza- the by missing analytical in This comparison 19] any differences direct Among 16, provided the a studies.[15, studies. part half the the in only in of least INR/PTT,[20] used use findings at in tests possible the INR/PTT change the interpreting the was and when of outcome statin[20] difficulties, tion of where in type studies in- result cholesterol the elevated six group[18] the regarding with control the and information patients the of statins from in lack to differs statins the levels of studies, response requiring cholesterol some pharmacological normal indication for treat- the Further, with trials, clinical that patients levels. clinical any in possible included without VKA two is patients with the It in teraction In 16] initiated 20] studies therapy.[15, was not.[15, two lowering atorvastatin or coagulation,[13,14],[16-19] cholesterol and excluded and were rosuvastatin excluded VKA patients with studies with these most ment interact whether While report could differed. acenocoumarol not that also the and did studies medication Furthermore, phenprocomarol included other the dose. warfarin, taking the in statin with patients population statins, and treatment patient with statin VKA the treatment Finally, of in initiating treatment. type patients treatment to concerned include VKA regard selection. studies to in with literature included designed patients heterogeneity, the strategies considerable concerned of validity showed search studies ensuring studies included systematic persons, the broad two all multiple by While assessed the was is literature study All our data. same of original of initiation.[13, bleeding. doses strength the reduced after GI primary fluvastatin) increases, with weeks The INR and hospitalization 4 as of of rosuvastatin, described risk about present, degree pravastatin, increased also peaks (atorvastatin, the and was seemingly slight VKA anticoagulation statins on a increased which studied slightly to initiation 0.15-0.65, of lead other statin tendency users from the warfarin of ranging in For effect treatment INR 14],[19] simvastatin the mean of initiation exploring in Overall, studies increase users. eight VKA in identified anticoagulation review systematic This considered not of was decrease decrease Discussion the significant However, treatment. statistically atorvastatin treatment. yet atorvastatin of of small initiation initiation important.[16] a treatment after after therapeutically for warfarin INR 3-5 days in except day 15 an from patients unchanged first seconds in 12 remained 1.6 the with resulted time time INR study prothrombin days prothrombin small an mean 14 mean A The experienced in to mg.[15] patients change 80 up five the to of remaining increased described and treatment was period the of initiation dosage a of Initiation rosuvastatin of out in when treatment. effect Four day warfarin the per patients. stable investigated rosuvastatin seven in study patients mg seven One 10 in with rosuvastatin respectively. and of rosuvastatin warfarin, increasement between and interaction dosage drug atorvastatin potential and the investigated warfarin treatment.[17] studies statin clinical of prospective two weeks Finally, 12 after respectively mg/day 0.11 and 4 > ihntenx 4days, 14 next the within 4 > ntooto the of out two in 4 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 Interaktionsdatabasen.dk. 10. MICROMEDEX. - search Interactions Drug 9. With Users Flucloxacillin. Lexicomp Warfarin or in 8. Dicloxacillin Embolism Systemic to and Exposed Stroke Replacement Ischemic Valve al. Ther Heart et or Z, statins. Ennis Fibrillation LC, Atrial with Lund M, associated Hellfritzsch statins. 7. of effects pharmacology Non-cardiovascular The CR. RS. Sirtori Blumenthal 6. SS, food Martin and CS, drug warfarin, 2014;349:1-10. Desai its between differences and Pharmacogenetic warfarin 5. B. of Wilffert overview T, Schalekamp phenprocoumon. Systematic JRBJ, and Brouwers acenocoumarol al. M, et Beinema R, 4. Labiris JA, Pereira AM, interactions. Holbrook Physicians Antagonists. 3. Chest K Vitamin of of College therapy Pharmacokinetics American anticoagulant Comparative 1246. Oral M. ed: G. Ufer Palareti 9th 2. EM, thrombosis, Hylek of guidelines. M, practice prevention Crowther clinical and A, evidence-based Wittkowsky therapy AS, Antithrombotic Gallus - W, Ageno 1. reasonable upon author corresponding the References from available are study this paper. of this findings request. the in support reported that work data the The to relation where no institution statement with availability the and to Data fees) paid personal funds (no with employed all was Pharma, he Boehringer- LEO unrelated Astra-Zeneca, and Astellas, Pharma Servier Almirall, Astellas Alcon, Nordisk, by and Novo T.B.S. funded Eisai Ingelheim, projects work. for research in submitted lectures participation paid the reports A.P. and outside Pfizer Pharma, for Astellas work. lectures and this paid Eisai, to and Pfizer, consulting from done fees has personal final reports the T.B.S. approved search. and literature read the authors All interests conducted manuscript. Competing also draft who first AOS, he with prepared together A.E. manuscript. reviewer work. and the author supervised A.P. principal the was A.E. Covidence. to guidance with help Contributors for be Burghle should Alaa monitoring acknowledge authors INR The of of initiation frequency of the treatment. effect if concomitant anticoagulant individually, Acknowledgements of The evaluated period be relevance. first should clinical the during it without increased and be anticoagulation vary, Considering in following to increase statins studies. effect considered reported included anticoagulant other overall the the increased warfarin, and in with an limited observed treated of patients was is tendency in treatment treatment VKA a simvastatin in of statins, while initiation and initiated VKA when of treatment, types statin different Despite ited. 2020;107:607-616. . ® rhItr Med Intern Arch rgItrcin UpToDate. - Interactions Drug 2005;165:1095-1106. . hobHaemost Thromb Chest hrao Res Pharmacol 2012;141:e44S-e88S. . 5 2008;100:1052-1057. . 2014;88:3-11. . lnPharmacokinet Clin lnPharmacol Clin 2005;44:1227- . BMJ . Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. eetrlvn oeta ulctosntietfidb u erhsrtg.Frhroe h interaction to the screening references. Furthermore, full-text Checker, additional Interaction for for strategy. Disagreements Stockleys reviewed search selected (www.interaktionsdatabasen.dk), were our publications Agency independently. Lexicomp/Uptodate.com Medicines by all and ALS) Danish Ti- identified in and the not references of (AEE references. databases publications searched additional doctors included. We potential identify medical pub- relevant not to two or were consensus. detect by screening language work by full-text screened reported regarding unpublished resolved for were and restrictions and were eligible abstracts no use, proceedings, were and imposed statin conference reviews We tles new Abstracts, studies, and herefore. search. original use proxies the Besides antagonist studies or on Eligible K INR date 2020. vitamin in lication 13, on changes February data until of inception presented outcomes from subjects, searched were human Embase included and PubMed databases The on patients X in Appendix search kinase literature creatine of Flowchart and 1. enzymes, Figure lipids, of Monitoring legends S. Figure Romeo improves inhibitor, C, therapy. reductase Pirazzi drug A O, lipid-lowering HMG-coenzyme Wiklund an Simvastatin, 24. RR. month. Taylor 1 drug D, within oxidative Green function on endothelial agents G, antifungal O’Driscoll the of 23. Effects DJ. Greenblatt of relevance. LL, Clinical characteristics Moltke analytical metabolism. Von of findings. K, study Venkatakrishnan reporting of Inadequate 22. replication Z. and interpretation Zhao to DB, threat 2019;65:1554-1562. Sacks A DE, . research: clinical Bruns Mining: in KJ, used Data Welsh biomarkers by Q, Interactions Sun Drug-Drug Identifying Interactions. 21. Drug al. Warfarin-Associated et of TSG, Study Sehested Pilot L, Danish A Clemmensen A PW, statins: Hansen and warfarin 20. between interaction Drug-drug in al. Initiation et BS, Fibrate/Statin study. Lind cohort S. ALO, Hennessy Svendsen AE, YX, Engell Yang 19. F, Risk. Wan Bleeding use CM, Gastrointestinal Statin and Brensinger WM. Users WB, Lijfering Warfarin Bilker FJM, H, Meer antagonists. Schelleman der K van 18. vitamin MJHA, Warfarin. of Kruip of users SM, Activity in Bonafacio Anticoagulant coagulation JS, the decreases Biedermann Alter N, Not Rein van Does 17. Atorvastatin on BJ. rosuvastatin GL of Pharmacol Gibson Effect Clin R, DW. J Abel Schneck R, G, Stern Gibson 16. K, Lasseter pharmacokinetics. PD, anticoagulation and Mitchell warfarin pharmacodynamics PD, on warfarin Martin co-medication SG, a simvastatin Simonson of anticoagulation: 15. effect warfarin The on requirements. H. dose simvastatin Wynne and H, of response Hickmott effect F, The Kamali 14. JD. study. Lindh cohort B, nationwide register-based Mannheimer meta-analysis Swedish and ML, review systematic Andersson for 13. items explanation. reporting and Preferred Elaboration al. 2015: et M, (prisma-p) Clarke meta-analysis protocols D, and Moher review L, systematic Shamseer for 12. items reporting Preferred statement. al. 2015 et M, (PRISMA-P) Clarke protocols L, Shamseer D, Moher 11. rJCi Pharmacol Clin J Br 1997;37:1062-1064. . urCrilRep Cardiol Curr lnPharmacokinet Clin hobHaemost Thromb ulse nie2020:1-6. online Published . Circulation e s urHmn Diet y Humana Nutr Esp Rev 2013;15:397. . u lnPharmacol Clin J Eur 1997;95:1126–1131. . 2003;89:949-950. . 2000;38:111-180. . mJMed J Am lnPharmacol Clin J 6 u lnPharmacol Clin J Eur BMJ icCrivs ulOutcomes Qual Cardiovasc Circ 2015;350:1-25. . 2010;123:151-157. . 2016;20:148-160. . 2005;45:927-934. . 2019;75:1387-1392. . 2016;72:1441-1447. . 2016;9:621-628. . lnChem Clin Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. rDpeain rTolmrlo auio acua rMrua rFltrmo atvno fluin- or Jantoven or Falithrom or (coumarin Marcumar 29. or coumatetralyl).mp. 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HMG-CoA*.mp. 22. hydroxymethylglutaryl*.mp. 21. rosuvastatin.mp. 20. fluindostatin.mp. 19. compactin.mp. 18. mevinolin.mp. 17. zocor.mp. 16. lipostat.mp. 15. pravachol.mp. 14. altocor.mp. 13. mevacor.mp. 12. lescol.mp. 11. baycol.mp. 10. lipitor.mp. 9. simvastatin.mp. 8. pravastatin.mp. 7. lovastatin.mp. 6. fluvastatin.mp. 5. cerivastatin.mp. 4. atorvastatin.mp. 3. statins).mp. or (statin inhibitor/ 2. reductase A coenzyme hydroxymethylglutaryl EMBASE exp in 1. strategy search full the of Example racenocumar or $ $ rcumarin or rcoumadin or $ $ rVAo VKAs).mp. or VKA or rphenprocoum or $ rflidoedoo hnnin rcoidoeo diphenadione).mp. or clorindione or phenindione dionor fluindione or $ rphenprocum or 7 $ rdicoumar or $ rdicumar or $ racenocoumar or $ Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. interactions-between-vitamin-k-antagonists-and-statins-a-systematic-review 1_310820.docx Table file Hosted 38 not 37 39. abstract conference to 37 limit 38. 36 33 not or studies) 35 32 animal or 37. and 31 (animals or to 30 35 or limit 29 36. or 28 34 or and 27 23 or 35. 26 or 25 or 24 34. ratio.mp. normalized international 33. ratio.mp. normalised international or 32. tintorane or tedicumar ratio/ or normalized international sofarin or warnerin).mp. 31. prothromadin or warfilone or panwarfin or warfant or panwarfarin or or waran marevan athrombin or lawarin or or aldocumar or (adoisine 30. vial at available https://authorea.com/users/312184/articles/478704-drug-drug- $ rcrno omfn rcuahn rjnoe rkumatox or jantoven or coumaphene or coumafene or carfin or k 8 Posted on Authorea 10 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159969839.93030821 — This a preprint and has not been peer reviewed. Data may be preliminary. 9