Prevention of Prevention of Periop MI: Where Periop MI: Where

are we now; & are we now; & where are we where are we

going?going?H YangH Yang

Department of Department of AnesthesiologyAnesthesiology

Perioperative IschemiaPerioperative Ischemia

nPre-op

(%)Intra-

op (%)Post-

op (%)

ManganoNEJM1990

474 20 25 40

RabyJAMA1992

115 20 18 30

POISE. Lancet 2008; 371:1839-47

POISE Primary Outcome EventsPOISE Primary Outcome Events

POISE. Lancet 2008; 371:1839-47

Ris

k

0.0

0.02

0.04

0.06

0.08

0 10 20 30

HR(95%CI)=0.83(0.70-0.99), p=0.035

4177 3915 3873 38534174 3959 3909 3879

# at Risk

MP

Metoprolol

Placebo

POISE Primary OutcomesPOISE Primary Outcomes

POISE. Lancet 2008; 371:1839-47

0.0

0.02

0.04

0.06

0.08

0 10 20 30 Days

Metoprolol

Placebo

HR(95%CI)=0.70(0.56-0.86), p=0.0007

4177 3923 3882 38594174 3976 3922 3889M

P

POISE Non-fatal MIPOISE Non-fatal MI

Ris

k

POISE. Lancet 2008; 371:1839-47

All DeathAll Death

Ris

k

0.0

0.01

0.02

0.03

0 10 20 30 Days

Metoprolol

Placebo

HR(95%CI)=1.33(1.02-1.74), p=0.032

4177 4116 4091 40694174 4113 4066 4038

No. at Risk

MP

POISE. Lancet 2008; 371:1839-47

Ris

k0.

00.

005

0.01

00.

015

0.02

0

0 10 20 30 Days

Metoprolol

Placebo

HR(95%CI)=2.17(1.26-3.73), p=0.005

4177 4102 4076 40554174 4085 4038 4011

No. at Risk

MP

POISE StrokesPOISE Strokes

POISE. Lancet 2008; 371:1839-47

Independent Predictors of Periop MIIndependent Predictors of Periop MI

Independent predictor Association with perioperative MIAdjusted Odds Ratio(95% confidence interval)

Every 10 bpm increase in baseline heart rate 1.29 (1.13-1.50)

Prior history of stroke 2.24 (1.20-4.20)

Undergoing major vascular surgery 2.21 (1.15-4.25)

Preoperative serum creatinine >175 mol/L (> 2.0 mg/dl)

4.33 (2.32-8.09)

Age per deciles increase 1.53 (1.20-1.95)

emergent/urgent surgery 2.94 (1.65-5.26)

clinically important bleeding 3.62 (2.07-6.36)

MI = myocardial infarction; bpm = beats per minute; clinically important bleeding (i.e., bleeding that was disabling or required > 2 units of blood)

POISE. Lancet 2008; 371:1839-47

2.20-5.412.20-5.413.453.45asymptomatic MIasymptomatic MI

1.78-6.151.78-6.153.313.31symptomatic MIsymptomatic MI

9.93-36.259.93-36.2518.9718.97strokestroke

1.14-2.441.14-2.441.671.67bleedingbleeding

1.37-3.321.37-3.322.132.13bradycardiabradycardia

3.62-6.813.62-6.814.974.97hypotensionhypotension

95% CI95% CIAdjusted ORAdjusted ORPredictorPredictor

Independent postoperative predictors of deathIndependent postoperative predictors of death

Lancet 2008; 371: 1839–47

1.19-4.041.19-4.042.192.19AFIBAFIB

1.44-6.661.44-6.663.103.10clopidogrelclopidogrel

1.07-4.451.07-4.452.182.18hypotensionhypotension

1.46-8.301.46-8.303.483.48bleedingbleeding

Postoperative predictorsPostoperative predictors

1.66-4.701.66-4.702.802.80stroke/TIAstroke/TIA

95% CI95% CIHRHRPreoperative predictorPreoperative predictor

60 strokes – 49 ischemic, 3 hemorrhagic, 8 uncertain60 strokes – 49 ischemic, 3 hemorrhagic, 8 uncertain

StrokeStroke

Where we areWhere we are

• CertainCertain– Incidence of Periop MI can be reduced with periop Incidence of Periop MI can be reduced with periop ββ--

blockersblockers

• ControversialControversial– Beta-blocker increases periop all-cause mortality & CVABeta-blocker increases periop all-cause mortality & CVA

• SoSo– Is it a problem with POISEIs it a problem with POISE– Is it the question of the right magic pillIs it the question of the right magic pill– Is there something else going on; i.e. postopIs there something else going on; i.e. postop

J Clin Pharmacol 2005; 45:6 - 24

Bioavailability of Metoprolol CRBioavailability of Metoprolol CR

• Bioavailability after first pass effectBioavailability after first pass effect– Metoprolol tartrate (conventional) 78%Metoprolol tartrate (conventional) 78%– Metoprolol succinate (CR) 71%Metoprolol succinate (CR) 71%

• Metoprolol CR 200 mg Metoprolol CR 200 mg

= metoprolol 65 mg q12h= metoprolol 65 mg q12h

J Clin Pharmcol 2005; 45:6 - 24

J Clin Pharm Ther 1997; 22:171-9

J Cardiac Failure 2001; 7:311 - 7

Clin Pharmacol Ther 2004; 76:536 – 44

• CYP2D6 genotypeCYP2D6 genotype– Impacts on cytochrome P450 & metoprolol metabolismImpacts on cytochrome P450 & metoprolol metabolism

• 50 HBP patients - No correlation between genotypes 50 HBP patients - No correlation between genotypes and BP or adverse effectsand BP or adverse effects

PharmacogenomicsPharmacogenomics

Pharmacogenomics 2009; 9:175 - 84

PharmacogenomicsPharmacogenomics

• 52 patients: 27 – 2 functional alleles; 22 – 1 function 52 patients: 27 – 2 functional alleles; 22 – 1 function allel; 3 no functional alleleallel; 3 no functional allele

• Median dose-adjusted S-metoprolol concentrations Median dose-adjusted S-metoprolol concentrations 6.3 & 3.2 X higher in 0 or 1 versus 2 functional alleles6.3 & 3.2 X higher in 0 or 1 versus 2 functional alleles

• ““no relationships between CYP2D6 genotype and no relationships between CYP2D6 genotype and dose or clinical effects could be shown”dose or clinical effects could be shown”

Clin Pharmacol Ther 2005; 78: 378 - 87

PharmacogenomicsPharmacogenomics

• 121 patients enrolled in prospective 6-week multi-121 patients enrolled in prospective 6-week multi-center study on metoprololcenter study on metoprolol– 5 ultra-rapid CYP2D6 metabolizers; 91 extensive 5 ultra-rapid CYP2D6 metabolizers; 91 extensive

metabolizers; 21 intermediate metabolizers; 4 poor metabolizers; 21 intermediate metabolizers; 4 poor metabolizersmetabolizers

– UMs 0.0088 ng/mL, EMS 0.047 ng/mL, IMs 0.34 ng/mL, and UMs 0.0088 ng/mL, EMS 0.047 ng/mL, IMs 0.34 ng/mL, and PMs 1.34 ng/mL (PMs 1.34 ng/mL (P P < .0001)< .0001)

• No association with BP or HRNo association with BP or HR• No association with side effects except cold No association with side effects except cold

extremities and sexual dysfunctiionextremities and sexual dysfunctiion

Pha

rmac

ogen

omic

sP

harmacokinetics

Pharmacodynamics

ΒΒ-blockers & strokes-blockers & strokes

• Cardiac Insufficiency Bisoprolol Study II (CIBIS II)Cardiac Insufficiency Bisoprolol Study II (CIBIS II)– Strokes 31 vs 16, p=0.04Strokes 31 vs 16, p=0.04

• Nordic Diltiazem Trial (NORDIL)Nordic Diltiazem Trial (NORDIL)– Diltiazem vs diuretics + Diltiazem vs diuretics + ββ-blockers for HBP-blockers for HBP– Fatal & non-fatal strokes 159 vs 196 (6.4 vs 7.9 events per Fatal & non-fatal strokes 159 vs 196 (6.4 vs 7.9 events per

1000 patient-years, 0.80 [0.65 – 0.99], p=0.04)1000 patient-years, 0.80 [0.65 – 0.99], p=0.04)

Lindholm et al. Lancet 2005; 366:1545 - 53

Meta-analysesMeta-analyses

• 13 RCTs (105,951 patients) comparing 13 RCTs (105,951 patients) comparing ββ-blockers -blockers with other antihypertensiveswith other antihypertensives

• 7 RCTs (27,443 patients) comparing 7 RCTs (27,443 patients) comparing ββ-blockers with -blockers with placeboplacebo

• Strokes RR 16% higher for Strokes RR 16% higher for ββ-blockers than for other -blockers than for other drugs (95% CI 4 – 30%)drugs (95% CI 4 – 30%)

• Strokes RR 19% lower for Strokes RR 19% lower for ββ-blockers than for -blockers than for placebo (95% CI 7 – 29%)placebo (95% CI 7 – 29%)

Where we are goingWhere we are going

• Other candidates for prophylaxisOther candidates for prophylaxis– StatinsStatins– Alpha-2 agonistsAlpha-2 agonists– ASAASA

Statins: MagicalStatins: Magical

• CancerCancerRosuvastatin induces apoptosis in cultured human papillary thyroid Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cellscancer cells

J Endocrinol. 2011/04/08 ePub

• Airway inflammationAirway inflammationInhibition of Inflammatory Mediators: Role of Statins in Airway Inhibition of Inflammatory Mediators: Role of Statins in Airway InflammationInflammation

Otolaryngol.Head Neck Surg. 2011/04/05 ePub

• AsthmaAsthmaStatins in the Treatment of Acute Ischemic StrokeStatins in the Treatment of Acute Ischemic Stroke

Curr.Pharm.Biotechnol. 2011/04/06 ePub

JACC 2007; 49(12):1272 - 8

ARMYDA-ACSARMYDA-ACS

• 171 ACS, NSTEMI, statin-naïve patients for 171 ACS, NSTEMI, statin-naïve patients for angioplastyangioplasty

• Atorvastatin 80 mg 12 hrs before & 40 mg 2 hrs Atorvastatin 80 mg 12 hrs before & 40 mg 2 hrs before PCI versus placebobefore PCI versus placebo

• RR reduction of MACE of 88%: 5% in atorvastatin; RR reduction of MACE of 88%: 5% in atorvastatin; 17% in placebo; 17% in placebo; p p = 0.01= 0.01

• Mostly driven by reduction in MI: 5% in atorvastatin; Mostly driven by reduction in MI: 5% in atorvastatin; 15% in placebo; 15% in placebo; p p = 0.04= 0.04

StatinsStatins

• Kertai et alKertai et al– Database cohort studyDatabase cohort study– 570 patients for AAA 1991 – 2001570 patients for AAA 1991 – 2001– 30-day mortality or MI in 51 (8.9%) patients30-day mortality or MI in 51 (8.9%) patients– O.R. 0.24 (0.11 – 0.54)O.R. 0.24 (0.11 – 0.54)

• Poldermans et alPoldermans et al– Case-controlled studyCase-controlled study– 2816 vascular patients 1991 – 20002816 vascular patients 1991 – 2000– Case subjects 160 (5.8%) mortality Case subjects 160 (5.8%) mortality – Control subjects 2 : 1Control subjects 2 : 1– O.R. 0.22 (0.10 – 0.47)O.R. 0.22 (0.10 – 0.47)

StatinsStatins

• ““Reduction in Cardiovascular Events after vascular Reduction in Cardiovascular Events after vascular surgery with Atorvastatin: a randomized trial”surgery with Atorvastatin: a randomized trial”– 50 atorvastatin: 50 placebo50 atorvastatin: 50 placebo– Cardiac deaths, non-fatal MI, unstable angina, strokesCardiac deaths, non-fatal MI, unstable angina, strokes

• 4 (8%) atorvastatin: 13 (26%) placebo (p = 0.031)4 (8%) atorvastatin: 13 (26%) placebo (p = 0.031)

• DECREASE IIIDECREASE III– 250:247 fluvastatin vs placebo + 250:247 fluvastatin vs placebo + ββ-blockers-blockers– Myocardial Ischemia: 27/250 (10.8%) fluvastatin vs 47/247 Myocardial Ischemia: 27/250 (10.8%) fluvastatin vs 47/247

(10.9%) placebo(10.9%) placebo– CV death: 4/250 (1.6%) fluvastatin vs 8/247 (3.2%) placeboCV death: 4/250 (1.6%) fluvastatin vs 8/247 (3.2%) placebo– MI: 8/250 (3.2%) fluvastatin vs 17/247 (6.9%) placeboMI: 8/250 (3.2%) fluvastatin vs 17/247 (6.9%) placebo

Atorvastatin & Postop CRPAtorvastatin & Postop CRP

• Group AAA (n=26): atorvastatin 7 days before, the Group AAA (n=26): atorvastatin 7 days before, the day of, and for 7 days postopday of, and for 7 days postop

• Grop PAA (n=17): placebo for 7 days before, Grop PAA (n=17): placebo for 7 days before, atorvastatin on the day of Sx, & for 7 days postopatorvastatin on the day of Sx, & for 7 days postop

• Grooup PPP (n=17): placebo at all timesGrooup PPP (n=17): placebo at all times• Primary Outcome: C-reactive Protein (CRP) levels at Primary Outcome: C-reactive Protein (CRP) levels at

48 hours48 hours

Neilipovitz et al. The Ottawa Hospital

Atorvastatin & CRPAtorvastatin & CRP

Neilipovitz et al. The Ottawa Hospital

Ann Surg 2009; 249:921 - 6

DECREASE IVDECREASE IV

• Bisoprolol & fluvastatinBisoprolol & fluvastatin– 2 X 2 open label factorial design2 X 2 open label factorial design– 1066 intermediate risk scheduled for non-cardiovascular Sx1066 intermediate risk scheduled for non-cardiovascular Sx– 264 bisoprolol; 265 fluvastatin; 269 combined Rx; 268 to 264 bisoprolol; 265 fluvastatin; 269 combined Rx; 268 to

double control; double control;

• ResultsResults– Bisoprolol lower incidnce of MI or cardiac death, 2.1% vs Bisoprolol lower incidnce of MI or cardiac death, 2.1% vs

6.0%, p = 0.0026.0%, p = 0.002– Fluvastatin lower incidence, 3.2% vs 4.9%, p = 0.17Fluvastatin lower incidence, 3.2% vs 4.9%, p = 0.17

JAMA 2004; 292:2585-90

Incidence of hospitalized Incidence of hospitalized rhabdomyolysisrhabdomyolysis

• 252460 patients treated with lipid lowering drugs252460 patients treated with lipid lowering drugs– Prevastatin, simvastatin, atorvastatin 0.44 per 100000Prevastatin, simvastatin, atorvastatin 0.44 per 100000– Cerivastatin 5.34 per 100000Cerivastatin 5.34 per 100000– Fibrate 2.82 per 100000Fibrate 2.82 per 100000– Combined prevastatin or simvastatin or atorvastatin with Combined prevastatin or simvastatin or atorvastatin with

fibrate 5.98 per 100000fibrate 5.98 per 100000– Combined cerivastatin with fibrate 1035 per 100000Combined cerivastatin with fibrate 1035 per 100000– Per year of Rx, NNT to see 1 case of rhabdomyolysis is Per year of Rx, NNT to see 1 case of rhabdomyolysis is

22727 with statin monotherapy22727 with statin monotherapy

NEJM 1988; 318(1):47 - 8

Am J Med 2003; 114:742-52

Prophylaxis with Prophylaxis with αα2 agonists2 agonists

• 1980 – 2002, randomized trials 1980 – 2002, randomized trials • Comparing preop, intraop, postop 48 hours Comparing preop, intraop, postop 48 hours • Use of clonidine, dexmedetomidine, or mivazerolUse of clonidine, dexmedetomidine, or mivazerol• ResultsResults

– 23 trials included23 trials included– Mortality RR 0.64 [0.42 – 0.99, p=0.05]Mortality RR 0.64 [0.42 – 0.99, p=0.05]– Myocardial ischemia RR 0.76 [0.63 – 0.91, p = 0.003]Myocardial ischemia RR 0.76 [0.63 – 0.91, p = 0.003]

POISE. Lancet 2008; 371:1839-47

Perioperative IschemiaPerioperative Ischemia

nPre-op

(%)Intra-

op (%)Post-

op (%)

ManganoNEJM1990

474 20 25 40

RabyJAMA1992

115 20 18 30

Anesthesiology 2010; 112:25 - 33

Acute Surgical Anemia Influences the Acute Surgical Anemia Influences the Cardioprotective Effects of Cardioprotective Effects of ββ--BlockadeBlockade• Retrospective Review of Records between Mar 2005 – Jun Retrospective Review of Records between Mar 2005 – Jun

2006, 12006, 1° outcomes: MI, non-fatal CA, in-hospital death° outcomes: MI, non-fatal CA, in-hospital death• Nadir Hb – lowest Hb in first 3 days postopNadir Hb – lowest Hb in first 3 days postop• 1:1 Propensity Analysis with matching1:1 Propensity Analysis with matching• 4387 patients with nadir Hb4387 patients with nadir Hb

– 1153 (26%) received 1153 (26%) received ββ-blockers (BB) within 24 hr postop-blockers (BB) within 24 hr postop– Propensity matching in 827Propensity matching in 827– Major cardiac event 54 (6.5%) in BB & 25 (3.0%) in non-BB (RR Major cardiac event 54 (6.5%) in BB & 25 (3.0%) in non-BB (RR

2.38; CI 1.43 – 3.96, p = 0.0009)2.38; CI 1.43 – 3.96, p = 0.0009)– Hb drop > 35% Hb drop > 35%

• BB: RR 3.5; CI 1.8 – 5.5, p<0.0001BB: RR 3.5; CI 1.8 – 5.5, p<0.0001• Non-BB: RR 2.17; CI 0.97 – 4.86, p=0.0533Non-BB: RR 2.17; CI 0.97 – 4.86, p=0.0533

Anesthesiology 2009; 111(5): 988-1001

NEJM 1999; 340:409 - 17

A MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL OF TRANSFUSION REQUIREMENTS IN CRITICAL CARE (TRICC)

• Transfusion strategies Transfusion strategies • Equivalency TrialEquivalency Trial• 416 liberal strategy (100 g/L); 413 restrictive strategy 416 liberal strategy (100 g/L); 413 restrictive strategy

(70 g/L)(70 g/L)• 30-day mortality 18.7 vs 23.3%, p=0.1130-day mortality 18.7 vs 23.3%, p=0.11• In-hospital mortality 22.2 vs 28.1%, p=0.05In-hospital mortality 22.2 vs 28.1%, p=0.05• Restrictive strategy much more prevalent since the Restrictive strategy much more prevalent since the

TRICC trialTRICC trial

Criticial Care Medicine 2007; 35(6):1509-16

Subgroup Analysis of TRICCSubgroup Analysis of TRICC

SummarySummary

• High RiskHigh Risk– Prophylactic Prophylactic ββ-blockers to reduce MI-blockers to reduce MI– Keep up HbKeep up Hb

• ““Unfinished Symphony”Unfinished Symphony”– StatinsStatins– Alpha-2 agonistsAlpha-2 agonists– ASAASA

• Postop CarePostop Care– HypotensionHypotension– BleedingBleeding– Others?Others?