Perioperative beta-blockers in noncardiac surgery: The evidence continues to evolve

Transcription

1 REVIEW CME CREDIT EDUCATIONAL OBJECTIVE: Reders will weigh the evidence for nd ginst the periopertive use of bet-blockers MUZAMMIL MUSHTAQ, MD Assistnt Professor of Clinicl Medicine, Interdisciplinry Stem Cell Institute, Division of Hospitl Medicine, University of Mimi Miller School of Medicine, Mimi, FL STEVEN L. COHN, MD Medicl Director, UHelth Preopertive Assessment Center; Director, UMH Medicl Consulttion Service; Professor of Clinicl Medicine, Division of Hospitl Medicine, University of Mimi Miller School of Medicine, Mimi, FL Periopertive bet-blockers in noncrdic surgery: The evidence continues to evolve ABSTRACT The effectiveness nd sfety of giving bet-blockers to ptients undergoing noncrdic surgery remin controversil. The use of these drugs in this clinicl scenrio incresed fter the publiction of two positive trils in the lte 1990s nd ws encourged by ntionl orgniztions nd clinicl guidelines. However, when severl subsequent studies filed to show benefit, recommendtions becme more limited nd use decresed. This pper reviews recent evidence for nd ginst the periopertive use of bet-blockers. KEY POINTS If ptients hve other indictions for bet-blocker therpy, such s history of hert filure, myocrdil infrction in the pst 3 yers, or tril fibrilltion, they should be strted on bet-blocker before surgery if time permits. Of the vrious bet-blockers, the crdioselective ones pper to be preferble in the periopertive setting. Bet-blockers my need to be strted t lest 1 week before surgery, titrted to control the hert rte, nd used only in ptients t high risk (Revised Crdic Risk Index score > 2 or 3) undergoing high-risk surgery. rophylctic use of bet-blockers in the P periopertive period is highly controversil. Initil studies in the 1990s were fvorble, but evidence hs been conflicting since then. The pendulum swung wy from routinely recommending bet-blockers fter the publiction of negtive results from severl studies, including the Periopertive Ischemic Evlution (POISE) tril in Highlighting this chnge in prctice, Cndin study 2 found tht the use of periopertive bet-blockde incresed between 1999 nd 2005 but subsequently declined from 2005 to However, there ws no pprecible chnge in this pttern fter the POISE tril or fter chnges in the Americn College of Crdiology guidelines in 2002 nd In 2008, Hrte nd Jffer reviewed the periopertive use of bet-blockers in noncrdic surgery in this journl. 4 Since then, number of met-nlyses nd retrospective observtionl studies hve reported vrible findings relted to specific bet-blockers nd specific complictions. In this pper, we review the rtionle nd recent evidence for nd ginst the periopertive use of bet-blockers s guidnce for internists nd hospitlists. Further clinicl trils re necessry to clrify the ongoing controversy, prticulrly regrding the risk of stroke, which ws incresed in the lrge Periopertive Ischemic Evlution (POISE) tril. doi: /ccjm POTENTIAL CARDIOPROTECTIVE EFFECTS OF BETA-BLOCKERS Myocrdil infrction nd unstble ngin re the leding crdiovsculr cuses of deth fter surgery. 5 These events re multifctoril. Some re cused by the stress of surgery, which precipittes physiologic chnges relted to in- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

2 PERIOPERATIVE BETA-BLOCKERS Bet-blockers do severl things tht my be beneficil in the periopertive setting flmmtory meditors, sympthetic tone, nd oxygen supply nd demnd; others re cused by cute plque rupture, thrombosis, nd occlusion. 6 Most periopertive infrcts re non- Q-wve events 7 nd occur within the first 2 dys fter the procedure, when the effects of nesthetics, pin, fluid shifts, nd physiologic chnges re gretest. Becuse multiple cuses my contribute to periopertive myocrdil infrction, single preventive strtegy my not be sufficient. 8,9 Bet-blockers do severl things tht my be beneficil in the periopertive setting. They reduce myocrdil oxygen demnd by decresing the force of contrction nd by slowing the hert rte, nd slowing the hert rte increses distolic perfusion time. 10 They suppress rrhythmis; they limit leukocyte recruitment, the production of free rdicls, metlloproteinse ctivity, monocyte ctivtion, relese of growth fctors, nd inflmmtory cytokine response; nd they stbilize plque. 11 Their long-term use my lso lter intrcellulr signling processes, thus improving cell survivl by decresing the expression of receptors for substnces tht induce poptosis. 12 INITIAL POSITIVE TRIALS Mngno et l 13 begn the bet-blocker trend in 1996 with study in 200 ptients known to hve coronry rtery disese or risk fctors for it who were undergoing noncrdic surgery. Ptients were rndomized to receive either tenolol orlly nd intrvenously, titrted to control the hert rte, or plcebo in the immedite periopertive period. The tenolol group hd less periopertive ischemi but no difference in short-term rtes of myocrdil infrction nd deth. However, the deth rte ws lower in the tenolol group t 6 months fter dischrge nd t 2 yers, lthough ptients who died in the immedite postopertive period were excluded from the nlysis. Although this finding did not pper to mke sense physiologiclly, we now know tht ptients my experience myocrdil injury without infrction fter noncrdic surgery, phenomenon ssocited with n incresed risk of deth in the short term nd the long term. 14 Preventing these episodes my be the explntion for the improved outcome. The DECREASE tril 15 (Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy) provided dditionl support for bet-blocker use. The ptients were t high risk, hd bnorml dobutmine stress echocrdiogrms, nd were undergoing vsculr surgery; 112 ptients were rndomized to receive either orl bisoprolol (strted 1 month before surgery, titrted to control the hert rte, nd continued for 1 month fter surgery) or plcebo. The study ws stopped erly becuse the bisoprolol group reportedly hd 90% lower rte of myocrdil infrction nd crdic deth 1 month fter surgery. However, the study ws criticized becuse the totl number of ptients enrolled ws smll nd the benefit ws much greter thn usul for ny phrmcologic intervention, thus clling the results into question. In follow-up study, 16 survivors continued to be followed while receiving bisoprolol or usul cre. The incidence of myocrdil infrction or crdic deth t 2 yers ws significntly lower in the group receiving bisoprolol (12% vs 32%, odds rtio [OR] 0.30, P =.025). Boersm et l, 17 in n observtionl study, nlyzed dt from ll 1,351 ptients scheduled for mjor vsculr surgery being considered for enrollment in the DECREASE tril. The DECREASE protocol required ptients to undergo dobutmine stress echocrdiogrphy if they hd one or more risk fctors (ge 70 or older, ngin, prior myocrdil infrction, congestive hert filure, tretment for ventriculr rrhythmi, tretment for dibetes mellitus, or limited exercise cpcity) or if their physicin requested it. Twenty-seven percent received bet-blockers. In multivrite nlysis, clinicl predictors of dverse outcome were ge 70 or older; current or prior history of ngin; nd prior myocrdil infrction, hert filure, or cerebrovsculr ccident. In ptients who hd fewer thn three clinicl risk fctors, bet-blocker use ws ssocited with lower rte of complictions (0.8% vs 2.3%). Dobutmine stress echocrdiogrphy hd miniml predictive vlue in this lowerrisk group, suggesting tht stress testing my not be necessry in this group if bet-blockers re used ppropritely. However, in ptients 502 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014

3 MUSHTAQ AND COHN who hd three or more risk fctors, this test did provide dditionl prognostic informtion; those without stress-induced ischemi hd lower event rtes thn those with ischemi, nd bet-blocker use further reduced those rtes, except in ptients with extensive ischemi (more thn five left ventriculr segments involved). The Revised Crdic Risk Index. Lee et l 18 devised n index to ssist in preopertive crdic risk strtifiction tht ws subsequently incorported into the 2007 Americn College of Crdiology/Americn Hert Assocition preopertive risk guidelines. (It does not, however, ddress the bet-blocker issue.) It consists of six independent risk-predictors of mjor crdic complictions derived from 4,315 ptients over ge 50 undergoing noncrdic surgery. The risk fctors, ech of which is given 1 point, re: Congestive hert filure bsed on history or exmintion Renl insufficiency (serum cretinine level > 2 mg/dl) Myocrdil infrction, symptomtic ischemic hert disese, or positive stress test History of trnsient ischemic ttck or stroke Dibetes requiring insulin High-risk surgery (defined s intrthorcic, intr-bdominl, or supringuinl vsculr surgery). Ptients with 3 or more points re considered to be t high risk, nd those with 1 or 2 points re considered to be t intermedite risk. The Americn College of Crdiology/Americn Hert Assocition preopertive crdic risk lgorithm subsequently included five of these six risk fctors (the type of surgery ws considered seprtely) nd mde recommendtions concerning noninvsive stress testing nd hert rte control. On the bsis of these studies, specilty societies, guideline committees, nd hospitls enthusisticlly recommended the prophylctic use of bet-blockers to decrese postopertive crdic complictions. when the results filed to show benefit. The trils used metoprolol, strted shortly before surgery, nd with no titrtion to control the hert rte. The MVS study 19 (Metoprolol After Vsculr Surgery) rndomized 496 ptients to receive metoprolol or plcebo 2 hours before surgery nd until hospitl dischrge or mximum of 5 dys fter surgery. The metoprolol dose vried by weight: ptients weighing 75 kg or more got 100 mg, those weighing between 40 nd 75 kg got 50 mg, nd those weighing less thn 40 kg got 25 mg. Overll effects t 6 months were not significntly different, but intropertive brdycrdi nd hypotension requiring intervention were more frequent in the metoprolol group. The POBBLE study 20 (Periopertive Bet Blockde) rndomized 103 ptients who hd no history of myocrdil infrction to receive either metoprolol 50 mg twice dily or plcebo from dmission to 7 dys fter surgery. Myocrdil ischemi ws present in one-third of the ptients fter surgery. Metoprolol did not reduce the 30-dy crdic mortlity rte, but it ws ssocited with shorter length of sty. The DIPOM tril 21 (Dibetic Postopertive Mortlity nd Morbidity) rndomized 921 dibetic ptients to receive long-cting metoprolol succinte controlled-relese/extended relese (CR/XL) or plcebo. Ptients in the metoprolol group received test dose of 50 mg the evening before surgery, nother dose 2 hours before surgery (100 mg if the hert rte ws more thn 65 bpm, or 50 mg if between 55 nd 65 bpm), nd dily therefter until dischrge or mximum of 8 dys. The dose ws not titrted to hert-rte control. Metoprolol hd no sttisticlly significnt effect on the composite primry outcome mesures of time to deth from ny cuse, cute myocrdil infrction, unstble ngin, or congestive hert filure or on the secondry outcome mesures of time to deth from ny cuse, deth from crdic cuse, nd nonftl crdic morbidity. After initil positive trils, prophylctic bet-blockers were recommended to decrese postopertive crdic complictions THREE NEGATIVE TRIALS OF METOPROLOL In 2005 nd 2006, two studies in vsculr surgery ptients nd nother in ptients with dibetes cst doubt on the role of bet-blockers ADDITIONAL POSITIVE STUDIES Lindenuer et l 22 retrospectively evluted the use of bet-blockers in the first 2 dys fter surgery in 782,969 ptients undergoing noncrdic surgery. Using propensity score mtch- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

4 PERIOPERATIVE BETA-BLOCKERS POISE: More ptients on metoprolol died or hd strokes thn in the plcebo group ing nd Revised Crdic Risk Index scores, they found lower rte of postopertive mortlity in ptients with three or more risk fctors who received bet-blocker. There ws no significnt difference in the group with two risk fctors, but in the lowest-risk group (with score of 0 to 1), bet-blockers were not beneficil nd my hve been ssocited with hrm s evidenced by higher odds rtio for deth, lthough this ws probbly rtifctul nd reflecting dtbse limittions. Fering et l, 23 in n observtionl cohort study of 272 ptients undergoing vsculr surgery, reported tht higher doses of betblockers nd tight hert-rte control were ssocited with less periopertive myocrdil ischemi, lower troponin T levels, nd better long-term outcome. THE POISE TRIAL: MIXED RESULTS The rndomized POISE tril, 1 published in 2008, compred the effects of extended-relese metoprolol succinte vs plcebo on the 30-dy risk of mjor crdiovsculr events in 8,351 ptients with or t risk of therosclerotic disese who were undergoing noncrdic surgery. The metoprolol regimen ws 100 mg 2 to 4 hours before surgery, nother 100 mg by 6 hours fter surgery, nd then 200 mg 12 hours lter nd once dily for 30 dys. The incidence of the composite primry end point of crdiovsculr deth, nonftl myocrdil infrction, nd nonftl crdic rrest t 30 dys ws lower in the metoprolol group thn in the plcebo group (5.8% vs 6.9%; P =.04), primrily becuse of fewer nonftl myocrdil infrctions. However, more ptients in the metoprolol group died of ny cuse (3.1% vs 2.3% P =.03) or hd stroke (1.0% vs 0.5% P =.005) thn in the plcebo group. The metoprolol group hd higher incidence of cliniclly significnt hypotension, brdycrdi, nd stroke, which could ccount for much of the increse in the mortlity rte. Sepsis ws the mjor cuse of deth in this group; hypotension my hve incresed the risk of infection, nd bet-blockers my hve potentited hypotension in ptients who were lredy septic. Also, the brdycrdic nd negtive inotropic effects of the bet-blocker could hve msked the physiologic response to systemic infection, thereby delying recognition nd tretment or impeding the norml immune response. One of the mjor criticisms of the POISE tril ws its ggressive dosing regimen (200 to 400 mg within 36-hour period) in ptients who hd not been on bet-blockers before then. Also, the drug ws strted only few hours before surgery. In ddition, these ptients were t higher risk of deth nd stroke thn those in other trils bsed on high bseline rte of cerebrovsculr disese, nd inclusion of urgent nd emergency surgicl procedures. STUDIES SINCE POISE The POISE tril results 1 prompted further questioning of the prophylctic periopertive use of bet-blockers. However, proponents of bet-blockers voiced serious criticisms of the tril, prticulrly the dosing regimen, nd continued to believe tht these drugs were beneficil if used ppropritely. The DECREASE IV tril. Dunkelgrun et l, 24 in study using bisoprolol strted pproximtely 1 month before surgery nd titrted to control the hert rte, reported beneficil results in intermedite-risk ptients. In their rndomized open-lbel study with 2 2 fctoril design, 1,066 ptients t intermedite crdic risk were ssigned to receive bisoprolol, fluvsttin, combintion tretment, or control therpy t lest 34 dys before surgery. Bisoprolol ws strted t 2.5 mg orlly dily nd slowly titrted up to mximum dose of 10 mg to keep the hert rte between 50 nd 70 bets per minute. The group of 533 ptients rndomized to receive bisoprolol hd lower incidence rte of crdic deth nd nonftl myocrdil infrction thn the control group (2.1% vs 6.0%, HR 0.34, P =.002). A potentil limittion of this study ws its open-lbel design, which might hve led to tretment bis. Updted guidelines. Bsed on the results from POISE nd DECREASE IV, the Americn College of Crdiology Foundtion/Americn Hert Assocition Tsk Force on Prctice Guidelines 25 published focused updte on bet-blockers in 2009 s n mendment to their 2007 guidelines on periopertive evlution nd cre for noncrdic surgery. The Europen Society of Crdiology 26 relesed similr but somewht more liberl guidelines (TABLE 1). 504 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014

5 MUSHTAQ AND COHN TABLE 1 Periopertive bet-blockde guidelines Clss of recommendtion Clss I (tretment should be given) Clss II (tretment is resonble) Clss IIb (tretment my be considered) Clss III (tretment should not be given) 2009 Americn College of Crdiology/ Americn Hert Assocition Europen Society of Crdiology 26 Bet-blockers should be continued if the ptient is lredy receiving bet-blocker (level of evidence C) Bet-blockers titrted to hert rte nd blood pressure re: Probbly recommended for vsculr surgery plus known coronry rtery disese or ischemi on preopertive stress testing (level of evidence B) Resonble for vsculr surgery plus more thn 1 clinicl risk fctor (level of evidence C) Resonble for intermedite-risk surgery plus coronry rtery disese or more thn 1 clinicl risk fctor (level of evidence C) Usefulness of bet-blockers is uncertin for ptients undergoing: Intermedite-risk or vsculr surgery with 1 clinicl risk fctor in the bsence of coronry rtery disese (level of evidence C) Vsculr surgery with no clinicl risk fctors (level of evidence B) Bet-blockers should not be given to ptients with bsolute contrindictions to them (level of evidence C) Routinely giving high-dose bet-blockers in the bsence of dose titrtion is not useful nd my be hrmful to ptients not currently tking bet-blockers who re undergoing noncrdic surgery (level of evidence B) Bet-blockers re recommended for those with known ischemic hert disese or ischemi on preopertive stress testing (level of evidence B) Recommended for high-risk surgery (level of evidence B) Continution recommended if previously treted with bet-blockers for ischemic hert disese, rrhythmis, or hypertension (level of evidence C) Should be considered in intermedite-risk surgery Consider continution if previously treted with bet-blocker for congestive hert filure with systolic dysfunction (level of evidence C) Bet-blockers my be considered: low-risk surgery + risk fctors Periopertive high-dose bet-blockers without titrtion re not recommended (level of evidence A) Bet-blockers re not recommended in low-risk surgery without risk fctors (level of evidence B) Levels of evidence: A = multiple popultions evluted, dt derived from multiple rndomized clinicl trils or met-nlyses; B = limited popultions evluted, dt derived from single rndomized tril or nonrndomized studies; C = very limited popultions evluted, only consensus opinion of experts, cse studies, or stndrd of cre London et l, 27 in n observtionl study published in 2013, found lower 30-dy overll mortlity rte with bet-blockers (reltive risk [RR] 0.73, 95% confidence intervl [CI] , P <.001, number needed to tret [NNT] 241), s well s lower rte of crdic morbidity (nonftl myocrdil infrction nd crdic deth), but only in nonvsculr surgery ptients who were on bet-blockers within 7 dys of scheduled surgery. Moreover, similr to the findings of Lindenuer et l, 22 only ptients with Revised Crdic Risk Index score of 2 or more benefited from betblocker use in terms of lower risk of deth, CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

6 PERIOPERATIVE BETA-BLOCKERS TABLE 2 Bet-blocker met-nlyses before nd fter the POISE tril Study (yer) Before POISE No. of trils No. of ptients Ischemi Reltive risk in bet-blocker groups Periopertive MI Overll mortlity Periopertive stroke Composite (MI/deth) Devereux et l, , McGory et l, Schouten et l, , Wiesbuer et l, , After POISE Bnglore et l, , Bouri et l, ( secure ) b 2 (DECREASE) 10,529 1,178 NR Guy et l, c 11,738 NR Di et l, ,180 NR Summry Beneficil Beneficil No effect Potentilly hrmful d Sttisticlly significnt b Not including the Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy (DECREASE) trils, 15,16 which hve been discredited c Noncrdic surgicl trils only d Including the POISE tril MI = myocrdil infrction; POISE = Periopertive Ischemic Evlution tril 1 wheres the lower-risk ptients did not: Risk score of 0 or 1 no ssocition Score of 2 RR 0.63, 95% CI , P <.001, NNT 105 Score of 3 RR 0.54, 95% CI , P <.001, NNT 41 Score of 4 or more RR 0.40, 95% CI , P <.001, NNT 18). Bet-blocker exposure ws ssocited with significntly lower rte of crdic complictions (RR 0.67, 95% CI , P <.001, NNT 339), lso limited to nonvsculr surgery ptients with risk score of 2 or 3. The Dnish Ntionwide Cohort Study 28 exmined the effect of bet-blockers on mjor dverse crdic events (MACE, ie, myocrdil infrction, cerebrovsculr ccident, nd deth) in 28,263 ptients with ischemic hert disese undergoing noncrdic surgery; 7,990 with hert filure nd 20,273 without. Betblockers were used in 53% of ptients with hert filure nd 36% of those without hert filure. Outcomes for ll of the bet-blocker recipients: MACE HR 0.90, 95% CI All-cuse mortlity HR 0.95, 95% CI Outcomes for ptients with hert filure if they received bet-blockers: MACE HR 0.75, 95% CI All-cuse mortlity HR 0.80, 95% CI There ws no significnt benefit from bet-blockers in ptients without hert filure. Outcomes for those ptients if they received bet-blockers: 506 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014

7 MUSHTAQ AND COHN MACE HR 1.11, 95% CI All-cuse mortlity HR 1.15, 95% CI However, in ptients without hert filure but with history of myocrdil infrction within the pst 2 yers, bet-blockers were ssocited with lower risk of MACE nd llcuse mortlity. In ptients with neither hert filure nor recent myocrdil infrction, bet-blockers were ssocited with n incresed risk of MACE nd ll-cuse mortlity. This difference in efficcy depending on the presence nd timing of prior myocrdil infrction is consistent with the 2012 Americn College of Crdiology/Americn Hert Assocition guidelines for secondry prevention, in which bet-blockers re given clss I recommendtion only for ptients with myocrdil infrction within the pst 3 yers. Met-nlyses nd outcomes A number of met-nlyses hve been published over the pst 10 yers, with conflicting results (TABLE 2). The divergent findings re primrily due to the different studies included in the nlyses s well s the strong influence of the POISE tril. 1 The studies vried in terms of the specific bet-blocker used, dose titrtion nd hert rte control, time of initition of bet-blocker use before surgery, type of surgery, ptient chrcteristics, comorbidities, biomrkers nd dignosis of myocrdil infrction, nd clinicl end points. In generl, these met-nlyses hve found tht prophylctic periopertive use of bet-blockers decreses ischemi nd tends to reduce the risk of nonftl myocrdil infrction. They vry on whether the overll mortlity risk is decresed. The met-nlyses tht included POISE 1 found n incresed incidence of stroke, wheres those tht excluded POISE found no significnt difference, lthough there ppered to be slightly more strokes in the bet-blocker groups. The bet-blocker controversy incresed even further when Dr. Don Poldermns ws fired by Ersmus Medicl Center in November 2011 for violtions of cdemic integrity involving his reserch, including the DE- CREASE trils. The most recent met-nlysis, by Bouri et l, 29 included nine secure trils nd excluded the DECREASE trils in view of the controversy bout their uthenticity. The nlysis showed n increse in overll mortlity s well s stroke, primrily becuse it ws hevily influenced by POISE. 1 In contrst, the DECREASE trils hd reported decresed risk of myocrdil infrction nd deth, with no significnt increse in stroke. The uthors concluded tht guideline bodies should retrct their recommendtions bsed on the fictitious dt without further dely. 29 Although the design of the DECREASE trils (in which bet-blockers were strted well in dvnce of surgery nd doses were titrted to chieve hert rte control) is physiologiclly more compelling thn those of the negtive trils, the results hve been questioned in light of the integrity issue. However, to dte, none of the published DECREASE trils hve been retrcted. Two other met-nlyses, 30,31 published in 2013, lso found decresed risk of myocrdil infrction nd incresed risk of stroke but no significnt difference in short-term ll-cuse mortlity. ARE ALL BETA-BLOCKERS EQUIVALENT? In vrious studies evluting specific betblockers, the more crdioselective gents bisoprolol nd tenolol were ssocited with better outcomes thn metoprolol. The ffinity rtios for bet-1/bet-2 receptors rnge from 13.5 for bisoprolol to 4.7 for tenolol nd 2.3 for metoprolol. 32 Blocking bet-1 receptors blunts tchycrdi, wheres blocking bet-2 receptors my block systemic or cerebrl vsodiltion. In ptients with nemi, bet-blockde in generl my be hrmful, but bet-2 blockde my be even worse. Bet-blockers were ssocited with n incresed risk of MACE (6.5% vs 3.0%) 33 in ptients with cute surgicl nemi if the hemoglobin concentrtion decresed to less thn 35% of bseline, nd incresed risks of hospitl deth (OR 6.65) nd multiorgn dysfunction syndrome (OR 4.18) with severe bleeding during ortic surgery. 34 In ddition, the pthwy by which the bet-blocker is metbolized my lso ffect outcome, with less benefit from bet-blockers metbolized by the CYP2D6 isoenzyme of the cytochrome P450 system. Individul vritions in CYP2D6 ctivity relted to genetics or drug interctions my result in insufficient or exces- To dte, none of the DECREASE trils hve been retrcted CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

8 PERIOPERATIVE BETA-BLOCKERS TABLE 3 Specific bet-blockers nd rtes of dverse periopertive outcomes Study Outcome Atenolol Bisoprolol Metoprolol No betblocker Redelmeier et l, Myocrdil infrction or deth 2.5% 3.2% Wllce et l, dy mortlity 1-yer mortlity 1% 7% 3% 13% Ashes et l, Stroke, myocrdil infrction, or deth 4.0% 6.2% 11.9% 2.2% Di et l, (met-nlysis) Mortlity Lowest Intermedite Highest b London et l, Mortlity 0.6% 1.1% 1.5% Odds rtio 1.42 (95% confidence intervl ) compred with tenolol b Odds rtio 2.66 (95% confidence intervl ) compred with tenolol In ptients with nemi, bet-blockde in generl my be hrmful, but bet-2 blockde my be even worse sive bet-blockde. Becuse metoprolol is the most dependent on this system, ptients using it my be more susceptible to brdycrdi. 35 Studies compring tenolol nd metoprolol found tht the tenolol groups hd fewer myocrdil infrctions nd deths 36 nd lower 30- dy nd 1-yer mortlity rtes 37 thn the groups on metoprolol. Studies compring the three bet-blockers found better outcomes with tenolol nd bisoprolol thn with metoprolol fewer strokes, 38,39 lower mortlity rte, 31 nd better composite outcome 39 (TABLE 3 nd TABLE 4). START THE BETA-BLOCKER EARLY, TITRATE TO CONTROL THE HEART RATE A number of studies suggest tht how long the bet-blocker is given before surgery my influence the outcome (TABLE 5). The best results were chieved when bet-blockers were strted pproximtely 1 month before surgery nd titrted to control the hert rte. Becuse this long led-in time is not lwys prcticl, it is importnt to determine the shortest time before surgery in which strting bet-blockers my be beneficil nd yet sfe. Some evidence suggests tht results re better when the bet-blocker is strted more thn 1 week preopertively compred with less thn 1 week, but it is unknown wht the minimum or optiml time period should be. If bet-blocker is strted well in dvnce of the scheduled surgery, there is dequte time for dose titrtion nd tighter hert rte control. Most of the studies demonstrting beneficil effects of periopertive bet-blockers used dose titrtion nd chieved lower hert rtes in the tretment group thn in the control group. A criticism of the MVs, 19 POBBLE, 20 nd DIPOM 21 trils ws tht the ptients did not receive dequte bet-blockde. The POISE tril 1 used much higher dose of metoprolol in n ttempt to ssure bet-blockde without dose titrtion, nd lthough the regimen decresed nonftl myocrdil infrctions, it incresed strokes nd the overll mortlity rte, probbly relted to excess brdycrdi nd hypotension. The trget hert rte should probbly be between 55 nd 70 bets per minute. RISK OF STROKE POISE 1 ws the first tril to note cliniclly nd sttisticlly significnt increse in strokes with periopertive bet-blocker use. Although no other study hs shown similr incresed risk, lmost ll reported higher number of strokes in the bet-blocker groups, lthough the bsolute numbers nd differences were smll nd not sttisticlly significnt. This risk my lso vry from one bet-blocker to nother (TABLE 4). 508 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014

9 MUSHTAQ AND COHN TABLE 4 Bet-blockers nd incidence of periopertive stroke Study Bet-blocker Titrted to hert rte? Strted < 7 dys before surgery? Stroke rte (%) Bet-blocker group Mngno et l, Atenolol Yes Yes 4% 1% Brdy et l, Metoprolol No Yes 3.8% 0% Plcebo group Yng et l, Metoprolol No Yes 2.0% 1.6% Juul et l, Metoprolol No Yes 0.4% 0% POISE, Metoprolol No Yes 1% 0.5% vn Lier et l, b Bisoprolol Yes No 0.5% 0.4% London et l, All bet-blockers Metoprolol Atenolol 0.40% 0.40% 0.23% 0.3% Andersson et l, Not specified 0.12% 0.2% Mshour et l, Ashes et l, Metoprolol Atenolol Bisoprolol Metoprolol Atenolol Bisoprolol 0.34% c 0.07% 0% 0.62% 0.35% 0.16% High dose used b Dt from the Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy (DECREASE) I, II, nd IV trils from c Odds rtio 4.2 for ll periopertive strokes, 3.3 for intropertive strokes 0.1% 0.1% The usul incidence rte of postopertive stroke fter noncrdic, noncrotid surgery is well under 1% in ptients with no prior history of stroke but increses to pproximtely 3% in ptients with previous stroke. 40 An observtionl study from the Dutch group reported very low incidence of stroke overll (0.02%) in 186,779 ptients undergoing noncrdic surgery with no significnt difference in those on chronic bet-blocker therpy. 41 The DE- CREASE trils, with totl of 3,884 ptients, lso found no sttisticlly significnt increse in stroke with bet-blocker use (0.46% overll vs 0.5% with bet-blocker), 42 which in this cse ws bisoprolol strted well in dvnce of surgery nd titrted to control the hert rte. Although the DECREASE dt re under suspicion, they seem resonble nd consistent with those of observtionl studies. Proposed mechnisms by which betblockers my increse stroke risk include the side effects of hypotension nd brdycrdi, prticulrly in the setting of nemi. They my lso cuse cerebrl ischemi by blocking cerebrl vsodiltion. This effect on cerebrl blood flow my be more pronounced with the less crdioselective bet-blockers, which my explin the pprent incresed stroke risk ssocited with metoprolol. WHAT SHOULD WE DO NOW? The evidence for the sfety nd efficcy of bet-blockers in the periopertive setting continues to evolve, nd new clinicl trils New trils re needed to resolve the controversy, prticulrly regrding the risk of stroke CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

10 PERIOPERATIVE BETA-BLOCKERS TABLE 5 Timing of bet-blocker initition before surgery nd outcomes Study Mngno et l, Poldermns et l, Brdy et l, Outcome Myocrdil infrction or deth t 2 yers Myocrdil infrction or deth t 28 dys Crdiovsculr events t 30 dys Myocrdil infrction, stroke, or deth Strt of bet-blocker before surgery < 1 week 1 4 weeks > 4 weeks 10% 21% 3.4% 34% Yng et l, Crdiovsculr events t 30 dys 10.1% 12% Juul et l, Crdiovsculr events in hospitl 21% 20% POISE, Dunkelgrun et l, Myocrdil infrction Stroke Deth Myocrdil infrction or deth t 30 dys 32% 13% 3.6% 1.0% 3.1% Flu et l, Troponin elevtion, stroke, deth 27% 15% 16% London et l, Wijeysunder et l, Di et l, Deth Myocrdil infrction or crdic rrest Myocrdil infrction Stroke Deth (30 dys) Deth (1 yer) Myocrdil infrction Stroke Deth 1.3% 0.8% 4.1% 0.7% 2.9% 7.8% 1.60 b 1.36 b 2.75 b Sttisticlly significnt difference between < 1 week nd > 4 weeks (odds rtio 1.49, P =.03) b Reltive risk compring strt of the bet-blocker < 1 week vs > 1 week before surgery 1.2% 0.5% 2.8% 0.5% 1.6% 5.9% No betblocker 34% 15% 5.1% 0.5% 2.3% 2.1% 6% 1.0% 0.8% 3.3% 0.6% 1.8% 6.4% 2.3% 2.1% re needed to clrify the ongoing controversy, prticulrly regrding the risk of stroke. If ptients hve other indictions for betblocker therpy, such s history of hert filure, myocrdil infrction in the pst 3 yers, or tril fibrilltion for rte control, they should be receiving them if time permits. If prophylctic bet-blockers re to be effective in minimizing periopertive complictions, it ppers tht they my need to be more crdioselective, strted t lest 1 week before surgery, titrted to control hert rte, nd used in high-risk ptients (Revised Crdic Risk Index score > 2 or 3) undergoing high-risk surgery. Idelly, lrge rndomized controlled tril using crdioselective bet-blocker strted in dvnce of surgery in ptients with Revised Crdic Risk Index score greter thn 2, undergoing intermedite or high-risk procedures, is needed to fully nswer the questions rised by the current dt. 510 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014

11 MUSHTAQ AND COHN REFERENCES 1. POISE Study Group; Devereux PJ, Yng H, Yusuf S, et l. Effects of extended-relese metoprolol succinte in ptients undergoing noncrdic surgery (POISE tril): rndomised controlled tril. Lncet 2008; 371: Wijeysunder DN, Mmdni M, Lupcis A, et l. Clinicl evidence, prctice guidelines, nd ß-blocker utiliztion before mjor noncrdic surgery. Circ Crdiovsc Qul Outcomes 2012; 5: Americn College of Crdiology; Americn Hert Assocition Tsk Force on Prctice Guidelines (Writing Committee to Updte the 2002 Guidelines on Periopertive Crdiovsculr Evlution for Noncrdic Surgery); Americn Society of Echocrdiogrphy; Americn Society of Nucler Crdiology; Hert Rhythm Society; Society of Crdiovsculr Anesthesiologists; Society for Crdiovsculr Angiogrphy nd Interventions; Society for Vsculr Medicine nd Biology; Fleisher LA, Beckmn JA, Brown KA, et l. ACC/AHA 2006 guideline updte on periopertive crdiovsculr evlution for noncrdic surgery: focused updte on periopertive bet-blocker therpy: report of the Americn College of Crdiology/Americn Hert Assocition Tsk Force on Prctice Guidelines (Writing Committee to Updte the 2002 Guidelines on Periopertive Crdiovsculr Evlution for Noncrdic Surgery) developed in collbortion with the Americn Society of Echocrdiogrphy, Americn Society of Nucler Crdiology, Hert Rhythm Society, Society of Crdiovsculr Anesthesiologists, Society for Crdiovsculr Angiogrphy nd Interventions, nd Society for Vsculr Medicine nd Biology. J Am Coll Crdiol 2006; 47: Hrte B, Jffer AK. Periopertive bet-blockers in noncrdic surgery: evolution of the evidence. Cleve Clin J Med 2008; 75: Mngno DT. Periopertive crdic morbidity. Anesthesiology 1990; 72: London MJ, Zugg M, Schub MC, Sphn DR. Periopertive bet-drenergic receptor blockde: physiologic foundtions nd clinicl controversies. Anesthesiology 2004; 100: Bdner NH, Knill RL, Brown JE, Novick TV, Gelb AW. Myocrdil infrction fter noncrdic surgery. Anesthesiology 1998; 88: Priebe HJ. Triggers of periopertive myocrdil ischemi nd infrction. Br J Anesth 2004; 93: Zugg M, Schub MC, Foëx P. Myocrdil injury nd its prevention in the periopertive setting. Br J Anesth 2004; 93: Zugg M, Schub MC, Psch T, Sphn DR. Modultion of bet-drenergic receptor subtype ctivities in periopertive medicine: mechnisms nd sites of ction. Br J Anesth 2002; 88: Lndesberg G. The pthophysiology of periopertive myocrdil infrction: fcts nd perspectives. J Crdiothorc Vsc Anesth 2003; 17: Yeger MP, Fillinger MP, Hettlemn BD, Hrtmn GS. Periopertive bet-blockde nd lte crdic outcomes: complementry hypothesis. J Crdiothorc Vsc Anesth 2005; 19: Mngno DT, Lyug EL, Wllce A, Tteo I. Effect of tenolol on mortlity nd crdiovsculr morbidity fter noncrdic surgery. Multicenter Study of Periopertive Ischemi Reserch Group. N Engl J Med 1996; 335: Botto F, Alonso-Coello P, Chn MT, et l. Myocrdil injury fter noncrdic surgery: lrge, interntionl, prospective cohort study estblishing dignostic criteri, chrcteristics, predictors, nd 30-dy outcomes. Anesthesiology 2014; 120: Poldermns D, Boersm E, Bx JJ, et l. The effect of bisoprolol on periopertive mortlity nd myocrdil infrction in high-risk ptients undergoing vsculr surgery. Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy Study Group. N Engl J Med 1999; 341: Poldermns D, Boersm E, Bx JJ, et l; Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy Study Group. Bisoprolol reduces crdic deth nd myocrdil infrction in high-risk ptients s long s 2 yers fter successful mjor vsculr surgery. Eur Hert J 2001; 22: Boersm E, Poldermns D, Bx JJ, et l; DECREASE Study Group (Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy). Predictors of crdic events fter mjor vsculr surgery: role of clinicl chrcteristics, dobutmine echocrdiogrphy, nd betblocker therpy. JAMA 2001; 285: Lee TH, Mrcntonio ER, Mngione CM, et l. Derivtion nd prospective vlidtion of simple index for prediction of crdic risk of mjor noncrdic surgery. Circultion 1999; 100: Yng H, Rymer K, Butler R, Prlow J, Roberts R. The effects of periopertive bet-blockde: results of the Metoprolol fter Vsculr Surgery (MVS) study, rndomized controlled tril. Am Hert J 2006; 152: Brdy AR, Gibbs JS, Greenhlgh RM, Powell JT, Sydes MR; POBBLE tril investigtors. Periopertive bet-blockde (POBBLE) for ptients undergoing infrrenl vsculr surgery: results of rndomized double-blind controlled tril. J Vsc Surg 2005; 41: Juul AB, Wetterslev J, Gluud C, et l; DIPOM Tril Group. Effect of periopertive bet blockde in ptients with dibetes undergoing mjor non-crdic surgery: rndomised plcebo controlled, blinded multicentre tril. BMJ 2006; 332: Lindenuer PK, Pekow P, Wng K, Mmidi DK, Gutierrez B, Benjmin EM. Periopertive bet-blocker therpy nd mortlity fter mjor noncrdic surgery. N Engl J Med 2005; 353: Fering HH, Bx JJ, Boersm E, et l. High-dose bet-blockers nd tight hert rte control reduce myocrdil ischemi nd troponin T relese in vsculr surgery ptients. Circultion 2006; 114(suppl 1):I Dunkelgrun M, Boersm E, Schouten O, et l; Dutch Echocrdiogrphic Crdic Risk Evlution Applying Stress Echocrdiogrphy Study Group. Bisoprolol nd fluvsttin for the reduction of periopertive crdic mortlity nd myocrdil infrction in intermedite-risk ptients undergoing noncrdiovsculr surgery: rndomized controlled tril (DECREASE-IV). Ann Surg 2009; 249: Americn College of Crdiology Foundtion/Americn Hert Assocition Tsk Force on Prctice Guidelines; Americn Society of Echocrdiogrphy; Americn Society of Nucler Crdiology; Hert Rhythm Society; Society of Crdiovsculr Anesthesiologists; Society for Crdiovsculr Angiogrphy nd Interventions; Society for Vsculr Medicine; Society for Vsculr Surgery; Fleisher LA, Beckmn JA, Brown KA, et l ACCF/AHA focused updte on periopertive bet blockde incorported into the ACC/AHA 2007 guidelines on periopertive crdiovsculr evlution nd cre for noncrdic surgery. J Am Coll Crdiol 2009; 54:e13 e Tsk Force for Preopertive Crdic Risk Assessment nd Periopertive Crdic Mngement in Non-crdic Surgery; Europen Society of Crdiology (ESC); Poldermns D, Bx JJ, Boersm E, et l. Guidelines for pre-opertive crdic risk ssessment nd periopertive crdic mngement in non-crdic surgery. Eur Hert J 2009; 30: London MJ, Hur K, Schwrtz GG, Henderson WG. Assocition of periopertive bet-blockde with mortlity nd crdiovsculr morbidity following mjor noncrdic surgery. JAMA 2013; 309: Andersson C, Mérie C, Jørgensen M, et l. Assocition of bet-blocker therpy with risks of dverse crdiovsculr events nd deths in ptients with ischemic hert disese undergoing noncrdic surgery: Dnish ntionwide cohort study. JAMA Intern Med 2014; 174: Bouri S, Shun-Shin MJ, Cole GD, Myet J, Frncis DP. Met-nlysis of secure rndomised controlled trils of bet-blockde to prevent periopertive deth in non-crdic surgery. Hert 2014; 100: Guy J, Ochroch EA. Bet-blocking gents for surgery: influence on mortlity nd mjor outcomes. A met-nlysis. J Crdiothorc Vsc Anesth 2013; 27: Di N, Xu D, Zhng J, et l. Different bet-blockers nd initition time in ptients undergoing noncrdic surgery: met-nlysis. Am J Med Sci 2014; 347: Bker JG. The selectivity of bet-drenoceptor ntgonists t the humn bet1, bet2 nd bet3 drenoceptors. Br J Phrmcol 2005; 144: Bettie WS, Wijeysunder DN, Krkouti K, et l. Acute surgicl nemi influences the crdioprotective effects of bet-blockde: single-center, propensity-mtched cohort study. Anesthesiology 2010; 112: Le Mnch Y, Collins GS, Ibnez C, et l. Impct of periopertive bleeding on the protective effect of bet-blockers during infrrenl ortic reconstruction. Anesthesiology 2012; 117: Bdgett RG, Lwrence VA, Cohn SL.Vritions in phrmcology of bet- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST

12 PERIOPERATIVE BETA-BLOCKERS blockers my contribute to heterogeneous results in trils of periopertive bet-blockde. Anesthesiology 2010; 113: Redelmeier D, Scles D, Kopp A. Bet blockers for elective surgery in elderly ptients: popultion bsed, retrospective cohort study. BMJ 2005; 331: Wllce AW, Au S, Cson BA. Periopertive bet-blockde: tenolol is ssocited with reduced mortlity when compred to metoprolol. Anesthesiology 2011; 114: Mshour GA, Shrifpour M, Freundlich RE, et l. Periopertive metoprolol nd risk of stroke fter noncrdic surgery. Anesthesiology 2013; 119: Ashes C, Judelmn S, Wijeysunder DN, et l. Selective bet1-ntgonism with bisoprolol is ssocited with fewer postopertive strokes thn tenolol or metoprolol: single-center cohort study of 44,092 consecutive ptients. Anesthesiology 2013; 119: Selim M. Periopertive stroke. N Engl J Med 2007; 356: vn Lier F, Schouten O, vn Domburg RT, et l. Effect of chronic betblocker use on stroke fter noncrdic surgery. Am J Crdiol 2009; 104: vn Lier F, Schouten O, Hoeks SE, et l. Impct of prophylctic betblocker therpy to prevent stroke fter noncrdic surgery. Am J Crdiol 2010; 105: Devereux PJ, Bettie WS, Choi PT, et l. How strong is the evidence for the use of periopertive bet blockers in non-crdic surgery? Systemtic review nd met-nlysis of rndomised controlled trils. BMJ 2005; 331: McGory ML, Mggrd MA, Ko CY. A met-nlysis of periopertive bet blockde: wht is the ctul risk reduction? Surgery 2005; 138: Schouten O, Shw LJ, Boersm E, et l. A met-nlysis of sfety nd effectiveness of periopertive bet-blocker use for the prevention of crdic events in different types of noncrdic surgery. Coron Artery Dis 2006; 17: Wiesbuer F, Schlger O, Domnovits H, et l. Periopertive bet-blockers for preventing surgery-relted mortlity nd morbidity: systemtic review nd met-nlysis. Anesth Anlg 2007; 104: Bnglore S, Wetterslev J, Prnesh S, Swhney S, Gluud C, Messerli FH. Periopertive bet blockers in ptients hving non-crdic surgery: met-nlysis. Lncet 2008; 372: Flu WJ, vn Kuijk JP, Chonchol M, et l. Timing of pre-opertive betblocker tretment in vsculr surgery ptients: influence on post-opertive outcome. J Am Coll Crdiol 2010; 56: Wijeysunder DN, Bettie WS, Wijeysunder HC, Yun L, Austin PC, Ko DT. Durtion of preopertive bet-blockde nd outcomes fter mjor elective noncrdic surgery. Cn J Crdiol 2014; 30: ADDRESS: Steven L. Cohn, MD, University of Mimi Miller School of Medicine, 1120 NW 14th St., CRB-1140, Mimi, FL 33136; e-mil: scohn@med.mimi.edu New series! SMART TESTING Your guide to rtionl dignostic testing Coming soon When does centrl nervous system imging hve vlue for n dult with hedches? Do ll ptients undergoing elective noncrdic surgery need preop resting 12-led ECG? C LEVELAN D CLINI C JOURNAL O FMEDICINE 512 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 NUMBER 8 AUGUST 2014