Do Statins Reduce Atrial Fibrillation After Coronary Artery Bypass Grafting?

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1 Do Sttins Reduce Atril Fibrilltion After Coronry Artery Bypss Grfting? Anil Pturi, MD, Amn Shukl, MD b, George Ebr, Ed.D c, Viet Nguyen, DO d, Steven Borzk, MD e Myo Clinic, Rochester, Minnesot, USA. b Clevelnd Clinic, Clevelnd, Ohio, USA. c JFK Medicl Center, Atlntis, Florid, USA. d Clevelnd Clinic, Weston, Florid, USA. e University of Mimi Miller School of Medicine, nd Chrles E. Schmidt College of Science, Florid Atlntic University, Boc Rton, Florid; Nov Southestern College of Medicine, Ft. Luderdle, Florid, USA. Abstrct Bckground Atril Fibrilltion (AF) is common postopertive compliction fter coronry rtery bypss grfting. There is contrdictory evidence s to whether pre-opertive sttin use lowers the incidence of postopertive AF. This study imed to ssess whether pre opertive sttin therpy prevents the post-opertive AF. Methods In this retrospective cohort study we used propensity score mtching nlysis to evlute the effect of preopertive tretment with sttins on postopertive tril fibrilltion. There were 427 mtched pirs of ptients. Primry outcome ws the incidence of postopertive AF. Secondry outcomes were 30 dy mortlity, stroke, myocrdil infrction nd length of hospitl sty Results The incidence of postopertive AF ws not different in the sttin users compred with the nonusers (123, 28.1%, versus 127, 29.7%, respectively; p = 0.764). The 30 dy mortlity (6, 1.4%, versus 8, 1.9%; p = 0.590), stroke (10, 2.3%, versus 8, 1.9%; p = 0.634), myocrdil infrction (2, 0.5%, versus 0, 0.0%; p = 0.499) nd length of hospitl sty in dys (11.8 ± 9.0, versus 11.9 ± 9.3; p = 0.544) did not differ significntly between the two groups. Conclusions In propensity-mtched cohort of ptients undergoing coronry bypss surgery, we could not demonstrte tht preopertive sttins were protective for the development of post opertive tril fibrilltion. Introduction Atril Fibrilltion (AF) is common post opertive compliction fter coronry rtery bypss grft surgery. The incidence of post-opertive AF is pproximtely 30% fter isolted coronry rtery bypss grfting (CABG), 40% fter vlve replcements or repir, nd pproximtely 50% fter combined procedures. 1-3 The etiology of postopertive AF is not well understood, lthough multiple mechnisms such s neurohormonl ctivtion, volume overlod, nd inflmmtion hve been proposed.4 Advnced ge, history of AF or COPD, vlve surgery, nd withdrwl of bet- Corresponding Address :Anil Pturi MD, Myo Clinic, Old Mrin Hll 2-115, 200 First Street SW, Rochester, MN, 55905, USA. Telephone No, MN Jul-Aug, 2011 Vol 4 Issue 2

2 blockers or ngiotensin-converting enzyme (ACE) inhibitors re other risk fctors for AF fter CABG surgery. 1-4 Post-opertive AF hs been shown to be ssocited with incresed risk of mortlity, morbidity, thromboembolic stroke, hemodynmic compromise, incresed cost of cre nd prolonged length of hospitl sty. 5-8 Mny studies hve investigted the benefits of phrmcologic prophylxis to reduce post-opertive AF, though AF remins persistent problem nd worthwhile trget to reduce morbidity nd length of sty fter open hert surgery. The nti-inflmmtory properties of sttins my hve protective effect on the development of tril fibrilltion. 9 Severl smll observtionl studies investigted the role of prior sttin use on the incidence of AF following open hert surgery10-11 nd in other clinicl settings. 9,12 These studies were limited in scope nd size, nd cme to differing conclusions. A recent met-nlysis ws published exmining pre-procedurl sttin use in ptients undergoing percutneous coronry revsculriztion, CABG, or noncrdic surgery. 13 Six studies rndomized 748 ptients before CABG nd ssessed postopertive tril fibrilltion, often s secondry endpoint, nd found tht AF ws significntly less in sttin pretreted ptients (73 of 376, 0.19) thn control or plcebo (137 of 372, 0.37, reltive risk 0.54, 95% CI ). 13 Becuse of the limittions of observtionl dt, s well s met-nlysis of smll trils with obvious heterogeneity, we sought to evlute the hypothesis tht preopertive sttins reduce AF using propensity mtching in lrge, prospectively collected cohort of ptients undergoing open hert surgery. MATERIALS AND METHODS Ptient Popultion All ptients undergoing open-hert surgery t JFK Hospitl, Atlntis, FL, re prospectively enrolled in the Society of Thorcic Surgeons Adult Crdic Surgery Dtbse (version 2.61). We identified ll ptients who underwent coronry rtery bypss grfting (CABG) without ny concomitnt procedure between Jnury 2005 nd December There were 1,467 ptients identified, of which 198 ptients hd previous history of tril fibrilltion or flutter, or in which the surgery ws performed off-pump, nd were excluded from the study smple. The remining 1,269 ptients, of which 842 (66.3%) received preopertive sttin therpy nd 427 (33.6%) did not, constituted the clinicl mteril for this comprtive nlysis. This study ws presented to the Institutionl Review Bord nd Wiver of Informed Consent ws grnted bsed on its retrospective nture nd lck of identity disclosure. Dt Mngement nd Sttisticl Anlysis Dt were collected by trined bstrctors concurrently or shortly fter hospitl dischrge. Dt were recorded in stndrd mnner using the Society of Thorcic Surgeons Adult Crdic Surgery Dtbse guidelines. Demogrphic nd clinicl dt re presented s frequency distributions nd simple percentges. Vlues of continuous vribles re expressed s men ± stndrd devition. Univrite nlysis of selected preopertive, intropertive nd postopertive discrete vribles ws ccomplished by chi-squre, the continuitydjusted chi-squre nlysis or 2-tiled Fisher exct test with the pproprite degrees of freedom to test for the equlity of proportions in the cse of ctegoricl vribles. Two-smple Student s t- tests (two-tiled) were used to test for the equlity of mens for continuous vribles. A logistic regression model ws used to clculte ech ptient s propensity score. 20 A score between 0 nd 1 ws generted nd used to summrize collection of covrites, indicting the likelihood of ptient receiving or not receiving sttin therpy preopertively. Using Rosenbum s 21 optiml mtching lgorithms, ptients who did not receive sttin therpy were then mtched to those who did. This pproch minimizes the overll distnce between observtions nd ws conducted using Mhlnobis distnce within propensity score clipers (no mtches outside the clipers). The ppliction of this mtching technique controls for potentil confounding vribles. Dt collected were nlyzed using the biosttisticl cpbilities of the Number Cruncher Sttisticl Systems (NCSS), Kysville, UT. A significnt difference between mesurements ws defined s p less thn or equl to Jul-Aug, 2011 Vol 4 Issue 2

3 RESULTS IOf 1,269 ptients undergoing isolted CABG surgery, 842 (66.3%) ptients were receiving preopertive sttin therpy nd 427(33.6%) were not on sttin therpy. Bseline chrcteristics of the study popultion re shown in Tble 1. Compred with the control group, the ptients receiving sttins hd higher prevlence of hypertension nd dibetes mellitus, ngiotensin-converting enzyme (ACE) inhibitor nd bet-blocker use. The incidence of postopertive tril fibrilltion (the period from rrivl in the intensive cre unit until hospitl dischrge) by univrite nlysis ws not sttisticlly different in the sttin users compred with the nonusers s shown in Tble 3 (264, 31.4% versus 127, 29.7% respectively; p: 0.557). To reduce the effect of tretment selection bis nd potentil confounding in this observtionl study, we used propensity score mtching nlysis to evlute the pure effect of preopertive tretment with sttins on end points. After propensity-score mtching ws performed for the entire popultion, there were 427 mtched pirs of ptients (Tble 2). In the mtched cohorts, there ws no significnt difference between the sttin nd the control group Tble 1 : Comprison of Preopertive Vribles by Ptient Group Study Nme Sttin No Sttin p-vlue No of Ptients (%) 842(100.0) 427 (100.0) 1 Mle 668 (79.3) 317 (74.7) TRENDS24 TRENDS24 50% Pcemker 31% ICD 19% CRT Allowed, but not required 5.5 hours Biotronik25 100% CRT Allowed, but not required 3.8 hours Femle 174 (20.7) 108 (25.3) Age ( men yers) Hypertension 701 (83.3) 317 (73.3) Dibetes Mellitus 333 (39.5) 123 (28.8) Renl Dysfunction 41 (4.9) 15 (3.5) COPD 76 (9.0) 46 (10.8) Ejection Frction (men)= Prior CABG 10 (1.2) 3 (0.7) ACEI / ARB 341 (40.5) 123 (28.8) Bet Blocker 681 (80.9) 312 (73.1) Perfusion Time (min) Grft to Right 178 (21.1) 88 (20.6) COPD: Chronic Obstructive Pulmonry Disese, ACEI: Angiotensin converting enzyme inhibitor, ARB: Angio- tensin receptor blocker. Numbers in prentheses re percentges 12 Jul-Aug, 2011 Vol 4 Issue 2

4 for ny covrite. In this popultion, clculted overll incidence of postopertive tril fibrilltion ws not different in the sttin users compred with the nonusers (123, 28.1%, versus 127, 29.7%, respectively; p = 0.764) (Tbles 3 nd 4.) Secondry outcomes were not ffected by prior sttin use (tble 5). DISCUSSION Despite the dvnce in crdic nesthesi, myocrdil protection, nd surgicl techniques, the incidence of postopertive AF remins high. Aside from estblished AF risk fctors such s dvnced ge, COPD, low ejection frction, nd others, inflmmtion nd oxidtive stress might be involved in the development, recurrence, nd persistence of tril fibrilltion. It hs been shown tht sttin therpy, in ddition to its ntitherosclerotic effects, my hve ntioxidnt 22 nd nti-inflmmtory properties nd my reduce the incidence of AF. The im of our study ws to evlute the ssocition between preopertive use of sttins nd postopertive incidence of tril fibrilltion in lrge propensity score mtched group of ptients who underwent isolted CABG. We found no sttisticlly significnt difference between the group on sttin therpy preopertively s compred to the ptients not on sttins in terms of post-opertive incidence of tril fibrilltion. When we nlyzed the independent predictors of postopertive incidence of tril fibrilltion using multivrite logistic regression mong the mtched popultion, preopertive sttin tretment hd no reltionship to the development of postopertive tril fibrilltion. prospective observtionl study by Amr et l 12 showed tht pre-opertive sttin use ws ssocited with more thn threefold reduction in the risk Tble 2 Comprison of Preopertive Vribles by Ptient Group Following Propensity Anlysis nd Mtching. Vribles Sttin No Sttin p-vlue No of Ptients (%) 427 (100.0) 427 (100.0) 1 Mle 329 (77.0) 317 (74.7) Femle 98 (23.0) 108 (25.3) Age ( men yers) Hypertension 323 (75.6) 313 (73.3) Dibetes Mellitus 125 (29.3) 123 (28.8) Renl Dysfunction 15 (4.9) 15 (3.5) COPD 43 (10.1) 46 (10.8) Ejection Frction 41 (4.9) 15 (3.5) Prior CABG 2 (0.5) 3 (0.7) ACEI / ARB 123 (28.3) 123 (28.8) Bet Blocker 319 (74.7) 312 (73.1) Perfusion Time 341 (40.5) 123 (28.8) Grft to Right Coronry Artery COPD: Chronic Obstructive Pulmonry Disese, ACEI: Angiotensin converting enzyme inhibitor, ARB: Angio- tensin receptor blocker. Numbers in prentheses re percentges 13 Jul-Aug, 2011 Vol 4 Issue 2

5 of AF fter noncrdic thorcic surgery. Mrin et l did show tht the sttin use ws relted to lower incidence of AF fter CABG (odds rtio 0.52, 95% confidence intervl , p = 0.038).10 but this study ws limited due to reltively smll smple size of 234 ptients. A lrge retrospective observtionl study by Miceli et l 11 however showed tht preopertive sttin use ws ssocited with significntly higher incidence of postopertive tril fibrilltion compred to no sttin tretment in ptients undergoing isolted coronry rtery bypss grfting. Thus observtionl trils, despite their susceptibility to confounding, do not come to consistent conclusion s to the prospective vlue of sttins to reduce AF post CABG. A recent met-nlysis performed structured literture review from the mid 1960s until Februry, 2010, to disclose ll studies tht exmined AF following coronry intervention, CABG nd noncrdic surgery. 13 This review identified 8 trils of sttins of which 6 reported the outcome of postopertive AF While the combined outcomes fvored sttins, the trils were heterogeneous with respect to size ( ptients) s well s type of surgery (off-pump or not specified). Only 3 trils identified postop AF s primry im. 14,16,18 While prospective rndomized trils represent the highest level of evidence, circumspection is wrrnted becuse of pst experience with pooled smll trils of nitrtes nd mgnesium showing mortlity reduction for cute MI, while lrger rndomized tril cme to different nd definitive conclusion.25 We therefore suggest tht met-nlysis of 6 smll heterogeneous trils my not yield definitive conclusions with certinty. Study Limittions: Propensity score nlysis, while useful method for reducing bis in observtionl studies when rndomiztion to tretment groups is not possible, is not substitute for lrge nd prospectively rndomized group of ptients to directly test the hypothesis. The study is limited by its design becuse it provides ssocitions, but not cuse nd effect. Only rndomized, controlled tril could permit conclusion tht sttins protect ginst post opertive AF. Nevertheless, our study is bsed on lrge smple size nd therefore reflects the generl popultion of ptients undergoing CABG. Another limittion of our study is the lck of informtion bout left tril enlrgement, timing nd dose of preopertive sttin tretment, durtion of preopertive sttin tretment, or postopertive vribles such s volume overlod or electrolyte imblnce (hypomgnesemi, hypoklemi) which re independent risk fctors for tril fibrilltion nd re necessrily limited in scope in dtbse nlysis. A selection bis might be present becuse there ws no uniform indiction for the use of sttins nd thus clinicl indexes (e.g., hypertension, dibetes mellitus, nd ejection frction) were ssocited with sttin use The occurrence of tril fibrilltion ws monitored for the durtion of hospitliztion, but this dur- tion ws vrible depending on the post-op length of sty of the ptients, though observtion bis is likely to hve influenced both groups similrly. Conclusions Tble 3 Comprison of Preopertive Vribles by Univrite Anlysis. Vribles Sttin No Sttin p-vlue No of Ptients (%) 842 (100.0) 427 (100) 1 Atril Fibrilltion 264 (31.4) 127 (29.7) Numbers in prentheses re percentges 14 Jul-Aug, 2011 Vol 4 Issue 2

6 Tble 4 Comprison of Preopertive Atril Fibrilltion fter Propensity Anlysis nd Mtching Vribles Sttin No Sttin p-vlue No of Ptients (%) 427 (100.0) 427 (100) 1 Atril Fibrilltion 123 (28.1) 127 (29.7) Numbers in prentheses re percentges In propensity-mtched cohort of ptients undergoing open hert surgery, we could not demonstrte tht preopertive sttins were protective for the development of postopertive tril fibrilltion. Since our findings differ from met-nlysis of fewer thn 900 ptients in 6 heterogeneous trils, firm conclusion must wit lrge, prospective tril. Disclosures None of the uthors hs finncil conflict of interest to report. There re no other disclosures for ny of the uthors. There ws no grnt support for the study. The uthors cknowledge the support nd guidnce of Ms. Jmie Kosik whose ssistnce ws invluble. References Tble 5 Secondry Outcomes fter Propensity Anlysis nd Mtching Vribles Sttin No Sttin p-vlue No of Ptients (%) 427 (100.0) 427 (100) 1 Deth (30 dys) 6 (1.4) 8 (1.9) Stroke 10 (2.3) 8 (1.9) Myocrdil Infrction 2 (0.5) 0 (0.0) Length of hospitl sty 11.8 ± ± Numbers in prentheses re percentges 1. Luer MS, Egle KA, Buckley MJ, DeSnctis RW. Atril fibrilltion following coronry rtery bypss surgery. Prog Crdiovsc Dis 1989; 31: Vecht RJ, Nicolides EP, Ikweuke JK, Lissides CH. Clery J, Cooper WB. Incidence nd prevention of suprventriculr tchyrrhythmis fter coronry bypss surgery. Int J Crdiol 1986; 13: Cox JL. A perspective of postopertive tril fibrilltion in crdic opertions. Ann Thorc Surg 1993; 56: Bker WL, White CM. Post-Crdiothorcic Surgery Atril Fibrilltion: A Review of Preventive Strtegies. The Annls of Phrmcotherpy 2007; 41: Hogue CW Jr, Hyder ML. Atril fibrilltion fter crdic opertion: risks, mechnisms, nd tretment. Ann Thorc Surg. 2000; 69: Weintrub WS, Jones EL, Crver J, Guyton R, Cohen C. Determinnts of prolonged length of hospitl sty fter coronry bypss surgery. Circultion 1989; 80: Tmis JE, Steinberg JS. Atril fibrilltion independently prowww.jfib.com 15 Jul-Aug, 2011 Vol 4 Issue 2

7 longs hospitl sty fter coronry rtery bypss surgery. Clin Crdiol 2000; 23: Villrel RP, Hrihrn R, Liu BC, Kr B, Lee VV, Elyd M, Lopez JA, Rsekh A, Wilson JM, Mssumi A. Postopertive Atril Fibrilltion nd Mortlity fter Coronry Artery Bypss Surgery. J Am Coll Crdiol 2004; 43: Adm O, Neuberger HR, Bohm M, Lufs U. Prevention of Atril Fibrilltion with 3-Hydroxy-3-Methylglutryl Coenzyme A Reductse Inhibitors. Circultion. 2008; 118: Mrin F, Pscul DA, Roldn V, Arribs JM, Ahumd M, Tornel PL, Oliver C, Gómez-Pln J, Lip GY, Vldés M.. Sttins nd postopertive risk of tril fibrilltion following coronry rtery bypss grfting. Am J Crdiol. 2006; 97: Miceli A, Fino C, Fiorni B, Yetmn M, Nryn P, Angelini GD, Cputo M.. Effects of Preopertive Sttin Tretment on the Incidence of Postopertive Atril Fibrilltion in Ptients Undergoing Coronry Artery Bypss Grfting. Ann Thorc Surg Jun; 87(6): Amr D, Zhng H, Heerdt PM, Prk B, Fleisher M, Thler H. Sttin use is ssocited with reduction in tril fibrilltion fter noncrdic thorcic surgery independent of C-rective protein. Chest. 2005; 128: Winchester DE, Wen X, Xie L, Anthony AB. Eficence of preprocedurl sttin therpy: met-nlysis of rndomized trils. J Am Coll Crdiol 2010; 56: Ptti G, Chello M, Cndur D, Psceri V, Ambrosio A, Covino E, Sciscio GD. Rndomized tril of torvsttin for reduction of postopertive tril fibrilltion in ptients undergoing crdic surgery: results of the ARMYDA-3 (Atorvsttin for Reduction of MYocrdil Dysrhythmi After crdic surgery) study. Circultion. 2006; 114: Mnncio VA, Iorio D, De Amicis V, Di Lello F, Musumeci F. Effect of rosuvsttin pretretment on myocrdil dmge fter coronry surgery: rndomized tril. J Thorc Crdiovsc Surg 2008; 136: Ji Q, Mei Y, Wng X, Sun Y, Feng J, Ci J, Xie S, Chi L. Effect of preopertive torvsttin therpy on tril fibrilltion following off-pump coronry rtery bypss grfting. Circ J 2009; 73: Chello M, Ptti G, Cndur D, Mstrobuoni S, Di Sciscio G, Agrò F, Crssiti M, Covino E. Effects of torvsttin on systemic inflmmtory response fter coronry bypss surgery. Crit Cre Med 2006; 34: Song YB, On YK, Kim JH, Shin DH, Kim JS, Sung J, Lee SH, Kim WS, Lee YT. The effects of torvsttin on the occurrence of postopertive tril fibrilltion fter off-pump coronry rtery bypss grfting surgery. Am Hert J 2008; 156:373.e9-373.e Tmyo E, Alonso O, Alvrez J, Cstrodez J, Flórez S, di Stefno S. Effects of simvsttin on cute-phse protein levels fter crdic surgery. Med Clin (Brc.) 2008; 130: Rosenbum PR, Rubin DB. The centrl role of the propensity score in observtionl studies for cusl effects. Biometrik 1983; 70: Rosenbum PR. Optiml mtching for observtionl studies. J Am Stt Assoc 1989; 84(408): Rosenson RS. Sttins in therosclerosis: lipid-lowering gents with ntioxidnt cpbilities. Atherosclerosis 2004; 173: Strndberg TE, Vnhnen H, Tikknen MJ. Effect of sttins on C-rective protein in ptients with coronry rtery disese. Lncet 1999; 353: Albert MA, Dnielson E, Rifi N, Ridker PM. Effect of sttin therpy on C-rective protein levels: the prvsttin inflmmtion/ CRP evlution (PRINCE): rndomized tril nd cohort study. JAMA 2001;286: Borzk S. Ridker PM. Discordnce between met-nlyses nd lrge-scle rndomized, controlled trils: exmples from the mngement of cute myocrdil infrction. Ann Internl Med 1995; 123(11): Jul-Aug, 2011 Vol 4 Issue 2