1. Staying Ahead of Cardiac Ischemia Glynne Stanley MB.ChB., FRCA Boston University School of Medicine 2 nd Annual Ellison Pierce Symposium Positioning Your ORs For The Future 2 nd Annual Ellison Pierce Symposium Positioning Your ORs For The Future

2. Summarize the scope of the problem Discuss perioperative myocardial infarction Discuss the literature on pharmacological intervention Try to Address the Beta-blocker dilemma! Summarize the scope of the problem Discuss perioperative myocardial infarction Discuss the literature on pharmacological intervention Try to Address the Beta-blocker dilemma! Objectives

3. Scope of the Problem Non-cardiac cases /year 30 million At risk 6 million MI’s50,000 Deaths20,000 Surgical cardiac deaths50% PMI incidence5.6% Cost / year20 billion Non-cardiac cases /year 30 million At risk 6 million MI’s50,000 Deaths20,000 Surgical cardiac deaths50% PMI incidence5.6% Cost / year20 billion

4. AHRQ AHA ACS ASA AORN AHRQ AHA ACS ASA AORN CDC CMS VA IHI JCAHO CDC CMS VA IHI JCAHO Goal: reduce surgical complications and mortality 25% by 2010.

7. Who is at risk? Lee’s Revised Cardiac Risk Index –High risk surgical procedure Intraperitoneal, intrathoracic, vascular –History of IHD History of MI, +ve ETT, angina, Q waves –History of CHF –History of cerebrovascular disease –Insulin therapy –Creatinine > 2.0mg/dl Lee’s Revised Cardiac Risk Index –High risk surgical procedure Intraperitoneal, intrathoracic, vascular –History of IHD History of MI, +ve ETT, angina, Q waves –History of CHF –History of cerebrovascular disease –Insulin therapy –Creatinine > 2.0mg/dl

8. Who is at risk? High risk surgery* no CAD 0.9% High risk surgery* w/ CAD 2.7% Vascular patient with CAD8.5% *thoracic, abdominal, head and neck High risk surgery* no CAD 0.9% High risk surgery* w/ CAD 2.7% Vascular patient with CAD8.5% *thoracic, abdominal, head and neck

9. Who is at risk? Risk of Major Cardiac Event POINTSCLASSRISK 0I0.4% 1II0.9% 2III6.6% 3 or moreIV11%

10. Some studies have suggested up to a 28 fold risk in next 6 months of another event 20% two year survival! This is a BIG DEAL! Some studies have suggested up to a 28 fold risk in next 6 months of another event 20% two year survival! This is a BIG DEAL! BUT…if a patient survives a PMI…

11. medlib.med.utah.edu/.../ MYOCARD/MI010.html Mechanisms of MI

12. Mechanisms of MI: Plaques Low-lipid, fibrous-capped plaques CollateralizationTachycardia Non-Q wave MI Stable (quiescent) Stable (quiescent) Unstable (vulnerable) Unstable (vulnerable) Inflamed, lipid-laden thin-capped plaques May appear benign Angiographically Rupture / Occlusion Q wave MI

13. Other factors –Sympathetic nervous system –Hypercoagulable state and thrombosis –Endothelial ischemia triggering spasm –Perioperative milieu –(Hypoxia and hypotension!) Other factors –Sympathetic nervous system –Hypercoagulable state and thrombosis –Endothelial ischemia triggering spasm –Perioperative milieu –(Hypoxia and hypotension!) Mechanisms of MI

14. Are PMI’s Different? Baseline ECG abnormalities Presence of diabetes, CHF and angina 50% SILENT! Frequently Non-Q wave Occur day of or day after surgery Long-term mortality is higher Concept of the troponin leak Baseline ECG abnormalities Presence of diabetes, CHF and angina 50% SILENT! Frequently Non-Q wave Occur day of or day after surgery Long-term mortality is higher Concept of the troponin leak

15. Landesberg et al. Continuous ECG monitoring and ST trend analysis and troponin-I Ischemia duration strongly associated with peak cTn-I level Ischemia preceded in all cases by heart rate increase Majority of ischemic events including those culminating in PMI started within 2 hours of the end of surgery Landesberg et al. Continuous ECG monitoring and ST trend analysis and troponin-I Ischemia duration strongly associated with peak cTn-I level Ischemia preceded in all cases by heart rate increase Majority of ischemic events including those culminating in PMI started within 2 hours of the end of surgery Are PMI’s Different?

16. Plaque rupture in 46% - 55% of patients* Time to death patterns: - Non-plaque rupture deaths within first 3 days - Plaque rupture deaths were evenly distributed up to 17 days post-op Plaque rupture in 46% - 55% of patients* Time to death patterns: - Non-plaque rupture deaths within first 3 days - Plaque rupture deaths were evenly distributed up to 17 days post-op *Cohen and Aretz, 1999 Dawood et al, 1996 Post-Mortem Studies

17. Are PMI’s Different? Similar mechanism as seen in non-surgical patients: - Lower grade coronary stenosis - Unstable/vulnerable plaques - Acute thrombosis with luminal occlusion - Poor collateralization Similar mechanism as seen in non-surgical patients: - Lower grade coronary stenosis - Unstable/vulnerable plaques - Acute thrombosis with luminal occlusion - Poor collateralization

18. But… many patients may have an infarction that is, at least in part, related to prolonged ischemia

19. Furthermore, the story may be even more sinister since troponin levels are only points on a continuum of myocardial damage.

20. Kim et al, studied 229 patients undergoing aortic, infra-inguinal vascular or amputation surgery –Troponins measured immediately post op and days 1, 2 and 3 –98 patients had Troponin cTn-I >0.35ng/ml (lower limit of detection) –Likelihood of death in the first 6 months increased dramatically as the troponin levels rise Kim et al, studied 229 patients undergoing aortic, infra-inguinal vascular or amputation surgery –Troponins measured immediately post op and days 1, 2 and 3 –98 patients had Troponin cTn-I >0.35ng/ml (lower limit of detection) –Likelihood of death in the first 6 months increased dramatically as the troponin levels rise

21. Troponin level (ng/ml) < 0.350.4 – 1.51.6 – 3.0> 3.0 Odds ratio for death (95% confidence interval) 1.01.34.34.9 Odd ratio of death in first 6 months of vascular surgery compared With perioperative troponin levels. (Kim et al, Circulation, 2002) Odd ratio of death in first 6 months of vascular surgery compared With perioperative troponin levels. (Kim et al, Circulation, 2002)

22. Landesberg et al. 447 patients for major vascular surgery Troponins measured postoperatively –A 1–5 year follow-up –Odds ratio for death increased steadily with post-operative troponin levels. Data for non-vascular surgery is needed to look at a broader risk population Troponins measured postoperatively –A 1–5 year follow-up –Odds ratio for death increased steadily with post-operative troponin levels. Data for non-vascular surgery is needed to look at a broader risk population

23. Early & Delayed Myocardial Infarction After Abdominal Aortic Surgery. (Le Manach et al, Anesthesiology, 2005) Intense troponin analysis 1,136 consecutive patients for AAA 163 patients (14%) had one abnormal cTnI –106 (10%) always < 1.5ng/ml (MD group) –57 had cTnI > 1.5ng/ml and were considered to have had a PMI 21 patients (2%) were early (EPMI) (mean 37hrs) 34 patients (3%) were delayed (DPMI) (mean 74hrs) Intense troponin analysis 1,136 consecutive patients for AAA 163 patients (14%) had one abnormal cTnI –106 (10%) always < 1.5ng/ml (MD group) –57 had cTnI > 1.5ng/ml and were considered to have had a PMI 21 patients (2%) were early (EPMI) (mean 37hrs) 34 patients (3%) were delayed (DPMI) (mean 74hrs)

24. Key points: Two distinct patterns of cTnI –EPMI rise in cTnI NOT preceded by period of MD (subinfarction) –DPMI preceded by > 24 hrs of increased cTnI ie subinfarction MD –If cTnI not risen by 48 hrs has a negative predictive value of 99.6% Key points: Two distinct patterns of cTnI –EPMI rise in cTnI NOT preceded by period of MD (subinfarction) –DPMI preceded by > 24 hrs of increased cTnI ie subinfarction MD –If cTnI not risen by 48 hrs has a negative predictive value of 99.6% Early & Delayed Myocardial Infarction After Abdominal Aortic Surgery. (Le Manach et al, Anesthesiology, 2005)

25. EPMI probably represents acute plaque deterioration and acute coronary occlusion DPMI probably represents prolonged ischemia of postulated by Landesburg (similar to unstable angina Class IIIA) Monitoring for low-level troponins in the early post-operative period may give a “Golden Period” of opportunity for optimization of care and reduction in MD and PMI EPMI probably represents acute plaque deterioration and acute coronary occlusion DPMI probably represents prolonged ischemia of postulated by Landesburg (similar to unstable angina Class IIIA) Monitoring for low-level troponins in the early post-operative period may give a “Golden Period” of opportunity for optimization of care and reduction in MD and PMI Early & Delayed Myocardial Infarction After Abdominal Aortic Surgery. (Le Manach et al, Anesthesiology, 2005)

26. Part II What has been done so far to affect outcome?

27. The Use of Beta-blockers in CAD Beta-blockers after AMI reduces mortality by 24% Only 50%-60% utilization of beta-blocker Highest risk patients have the best response Beta-blockers after AMI reduces mortality by 24% Only 50%-60% utilization of beta-blocker Highest risk patients have the best response

28. Reduced Hemodynamic Stress ??? Platelet Action ??? Metabolic Increased Diastole Improved myocardial blood flow Decreased Ventricular Arrhythmias Reduced VF threshold Spectrum of potential benefits of beta-blockade Spectrum of potential benefits of beta-blockade Plaque stabilization Antiarrhythmic action Improved oxygen supply/demand

29. Perioperative Beta-blockers Randomized, double-blind, placebo controlled trial of 200 patients Intravenous atenolol 30 mins pre-op and post-op for up to 7 days 2 year mortality for atenolol group 10% vs. 21% in control (p=0.019) Combined cardiac outcomes similar reduction Randomized, double-blind, placebo controlled trial of 200 patients Intravenous atenolol 30 mins pre-op and post-op for up to 7 days 2 year mortality for atenolol group 10% vs. 21% in control (p=0.019) Combined cardiac outcomes similar reduction Mangano and Wallace. NEJM, 1996

30. Beta-blockers Atenolol shown to reduce incidence of Holter monitored perioperative ischemia Ischemia reductions associated with reduced risk of death at 2 year point. Atenolol shown to reduce incidence of Holter monitored perioperative ischemia Ischemia reductions associated with reduced risk of death at 2 year point. Wallace, Anesthesiology, 1998

31. Beta-blockers in Major Vascular Surgery Positive dobutamine echocardiography –Bisoprolol started an average of 37 days before surgery –Death from cardiac causes or non-fatal PMI 34% in untreated group and 3.4% in the bisoprolol group –In-hospital mortality significantly reduced Positive dobutamine echocardiography –Bisoprolol started an average of 37 days before surgery –Death from cardiac causes or non-fatal PMI 34% in untreated group and 3.4% in the bisoprolol group –In-hospital mortality significantly reduced Poldermans, NEJM, 1999

32. Beta-blockers May reflect the higher risk patient population, already pre-selected by non-invasive testing The authors suggest that it may be acceptable in many cases for the prophylactic use of a beta blocker to replace non-invasive testing May reflect the higher risk patient population, already pre-selected by non-invasive testing The authors suggest that it may be acceptable in many cases for the prophylactic use of a beta blocker to replace non-invasive testing

33. Beta-blockers 1351 patients for vascular surgery 1097 had DSE Categorized by risk factors and NWMAs Allows rationalization of testing High risk subset not helped 1351 patients for vascular surgery 1097 had DSE Categorized by risk factors and NWMAs Allows rationalization of testing High risk subset not helped Poldermans, JAMA, 2001

34. Cardiac Complications. % 0 5 10 1.2 0 4/327 0/48 0 5 10 3.0 0.9 16/528 2/215 0 5 10 5.8 2.0 6/103 1/50 0 5 33 2.8 6/18 1/36 0 5 33 36 5/15 4/11 Determine Risk Score Assign 1 Point for Each of the Following Characteristics: Age 70 years, Current Angina, Prior Myocardial Infarction, Congestive Heart Failure, Prior Cerebrovascular Event, Diabetes Mellitus and Renal failure 0 < Score < 3 (55%)Score – 0 (28%) Score 3 (17%) Dobutamine Stress Echocardiography (DSE) No New Wall-Motion Abnormalities (11%) New Wall-Motion Abnormalities in 1-4 segments (4%) New Wall-Motion Abnormalities in 5 segments (2%) Non β Blocker use β Blocker use

35. BUT NOT EVERYONE IS CONVINCED ! A number of negative studies and commentaries have emerged

36. Beta-Blockers Adverse Effects Withdrawal phenomena Bradycardia 28% Hypotension and pulmonary edema High conduction abnormalities Withdrawal phenomena Bradycardia 28% Hypotension and pulmonary edema High conduction abnormalities

37. Are the recommendations to use perioperative beta-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence? ( Devereaux PJ et al, CMAJ 2004) Very critical of original Atenolol trial Very skeptical about Poldermann’s data Very cautious about recommended beta- blockers to intermediate-risk and low-risk groups Very critical of original Atenolol trial Very skeptical about Poldermann’s data Very cautious about recommended beta- blockers to intermediate-risk and low-risk groups

38. Metoprolol After Vascular Surgery. ( Yang H, et al Can J Anesth 2004;51) ~500 patients randomly assigned to metoprolol or placebo in patients undergoing vascular surgery No significant benefit: 1 major event averted for every 50 patients treated and this result was not significant (p=0.4) Rate was not controlled ~500 patients randomly assigned to metoprolol or placebo in patients undergoing vascular surgery No significant benefit: 1 major event averted for every 50 patients treated and this result was not significant (p=0.4) Rate was not controlled

39. Randomized, Blinded Trail on Perioperative Metoprolol Versus Placebo for Diabetic Patients Undergoing Noncardiac Surgery. (Juul AB Et Al. AHA Scientific Sessions 2004) 921 patients with diabetes randomly assigned to metoprolol or placebo Similar rates of death or cardiovascular complications at 18-month follow-up But… –surgeries relatively low risk –Co-morbidities of population other than DM low –Inconsistent and relatively low metoprolol dosing –Wide confidence interval 921 patients with diabetes randomly assigned to metoprolol or placebo Similar rates of death or cardiovascular complications at 18-month follow-up But… –surgeries relatively low risk –Co-morbidities of population other than DM low –Inconsistent and relatively low metoprolol dosing –Wide confidence interval

40. Effect of chronic beta-blockade on perioperative outcome in patients undergoing noncardiac surgery: an analysis of observational and case control studies. (Giles JW et al. Anaesthesia, 2004) 18 studies of chronic beta-blocker use and non-coronary surgery No studies demonstrated protective effect Beta-receptor up-regulation Ischemia demonstrated at lower HR Perils of beta-blocker withdrawal clear 18 studies of chronic beta-blocker use and non-coronary surgery No studies demonstrated protective effect Beta-receptor up-regulation Ischemia demonstrated at lower HR Perils of beta-blocker withdrawal clear

41. Chronic beta-blocker use Herlitz et al. Cardiology 1995 –3504 patients presenting with acute MI –No difference in mortality at 1 month between those on chronic beta-blockers and those who were not ?? Up-regulation of beta-receptors Obvious perioperative parallels Herlitz et al. Cardiology 1995 –3504 patients presenting with acute MI –No difference in mortality at 1 month between those on chronic beta-blockers and those who were not ?? Up-regulation of beta-receptors Obvious perioperative parallels

42. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery; results of a randomized double-blind controlled trial. (Brady AR et al. J Vasc Surg. 2005 Apr;41.) No effect seen….. But with only 103 patients they had less than a 1 in 3 chance of seeing a 50% effect which is an optimistic expectation Study is really not contributory No effect seen….. But with only 103 patients they had less than a 1 in 3 chance of seeing a 50% effect which is an optimistic expectation Study is really not contributory

43. Perioperative Beta-Blocker Therapy and Mortality after Major Non Cardiac Surgery (Lindenauer et al, NEJM July 2005) Massive observational study Matched 119,632 patients to controls Looked at Beta-blocker use by including patients who “first” received the drug during the 1 st or 2 nd day of hospital stay Classified patients according to the Revised Cardiac Risk Index (RCRI) Massive observational study Matched 119,632 patients to controls Looked at Beta-blocker use by including patients who “first” received the drug during the 1 st or 2 nd day of hospital stay Classified patients according to the Revised Cardiac Risk Index (RCRI)

44. If RCRI was 3 or greater the risk reduction was up to 43% (in keeping with the main studies in the area) If RCRI was 2 then there no clear benefit However, in groups with RCRI of 0 and 1, there was no benefit from beta-blockers and even possible harm. If RCRI was 3 or greater the risk reduction was up to 43% (in keeping with the main studies in the area) If RCRI was 2 then there no clear benefit However, in groups with RCRI of 0 and 1, there was no benefit from beta-blockers and even possible harm. Perioperative Beta-Blocker Therapy and Mortality after Major Non Cardiac Surgery (Lindenauer et al, NEJM July 2005)

45. Data is large but still retrospective and very hard to control (although rigorous analysis was used) Beta-blocker use in the first 2 days may have been in response to problems in patients with low RCRIs No knowledge of heart rate control NO KNOWLEDGE OF BETA BLOCKER WITHDRAWAL Data is large but still retrospective and very hard to control (although rigorous analysis was used) Beta-blocker use in the first 2 days may have been in response to problems in patients with low RCRIs No knowledge of heart rate control NO KNOWLEDGE OF BETA BLOCKER WITHDRAWAL Perioperative Beta-Blocker Therapy and Mortality after Major Non Cardiac Surgery (Lindenauer et al, NEJM July 2005)

46. PeriOperative ISchemic Evaluation (POISE) randomized controlled trial, comparing metoprolol and placebo started a few hours preoperatively and continuing for 30 days in non cardiac surgery. 10,000 patients All risk groups Again probably not large enough to show a difference in those with 1 or NO risk factors 10,000 patients All risk groups Again probably not large enough to show a difference in those with 1 or NO risk factors

47. So what are we left with?? The lower risk groups are a dilemma Risk reduction, if any, is much less BUT…They comprise a large number of patients So in absolute terms many patients may still benefit Common sense approach may be all we end up with!! The lower risk groups are a dilemma Risk reduction, if any, is much less BUT…They comprise a large number of patients So in absolute terms many patients may still benefit Common sense approach may be all we end up with!!

48. Alpha-2 Agonists Mivazerol Dexmedetomidine Clonidine Mivazerol Dexmedetomidine Clonidine

49. Survival for clonidine-treated versus placebo-treated patients. Survival curves for 2 yr after surgery for 290 patients treated with clonidine (n = 125) and placebo (n = 65). Clonidine reduced the incidence of death (P = 0.01 by log-rank test and P = 0.01 by Wilcoxon test). Wallace: Anesthesiology, Volume 101(2).August 2004.284-293

51. Statins Mortality in statin group 8% vs 25%* Cardiac events in placebo group 26% vs. 8%** *Poldermans et al, Circ., 2003 **Durazzo et al, J Vasc Surg, 2003 Mortality in statin group 8% vs 25%* Cardiac events in placebo group 26% vs. 8%** *Poldermans et al, Circ., 2003 **Durazzo et al, J Vasc Surg, 2003

52. Statins Possible mechanisms of protection –Attenuate plaque inflammation –Induce plaque stability –Antithrombogenic –Antiproliferative –Inhibition of plaque leukocyte adhesion Possible mechanisms of protection –Attenuate plaque inflammation –Induce plaque stability –Antithrombogenic –Antiproliferative –Inhibition of plaque leukocyte adhesion

53. DECREASE – IV TRIAL ONGOING STUDY 6000 patients Non-cardiac/vascular and not minor surgery Fluvastatin and bisoprolol Four groups of patients Results expected Spring 2008 ONGOING STUDY 6000 patients Non-cardiac/vascular and not minor surgery Fluvastatin and bisoprolol Four groups of patients Results expected Spring 2008

54. CABG / PTCA Prior to Surgery Risk of CABG - Neurocognitive defects 95% - Stroke 3.0% - Death 3.2% Risk of death from non-cardiac surgery after CABG is 1.5% CARP Trial –No benefit from prophylactic CABG Risk of CABG - Neurocognitive defects 95% - Stroke 3.0% - Death 3.2% Risk of death from non-cardiac surgery after CABG is 1.5% CARP Trial –No benefit from prophylactic CABG

55. Does Pre-op PTCA or PTI Help? Stent < 6 weeks before non-cardiac surgery MI 18% Bleeding 28% Death in 20% When stent placed 1 day before surgery: - mortality 100%! Stent < 6 weeks before non-cardiac surgery MI 18% Bleeding 28% Death in 20% When stent placed 1 day before surgery: - mortality 100%! Grzegorz, et al. FACC 2000

56. Part III

57. Current Recommendations ??? APSF, Summer 2002: The evidence for perioperative beta-blocker therapy justifies… “immediate and widespread implementation” APSF, Summer 2002: The evidence for perioperative beta-blocker therapy justifies… “immediate and widespread implementation”

58. Current Practice ??? 95% aware of the literature 93% believe it 57% administer prophylactic beta blockers 9% admitted to a formal protocol 95% aware of the literature 93% believe it 57% administer prophylactic beta blockers 9% admitted to a formal protocol Van DenKerkhof et al, Anesth.Analg 2003

59. Current Recommendations Poldermans & Boersma. NEJM July, 2005 “….pending the availability of data (from ongoing trials) we believe it is appropriate to continue beta-blocker therapy in patients at low or intermediate risk…further information is needed before perioperative use of beta-blockers should be considered routinely in other patients at low or intermediate risk.” Poldermans & Boersma. NEJM July, 2005 “….pending the availability of data (from ongoing trials) we believe it is appropriate to continue beta-blocker therapy in patients at low or intermediate risk…further information is needed before perioperative use of beta-blockers should be considered routinely in other patients at low or intermediate risk.”

60. Cardiac Risk Reduction Therapy Copyright 2003 Art Wallace, MD PhD

62. Refer to Cardiology Aortic Stenosis Congestive Heart Failure Unstable Angina New Onset Angina Change in Anginal Pattern Angina without Medical Therapy PTCA or Stent Proceed with Surgery Coronary Artery Disease Patient Scheduled for Surgery With Peripheral Vascular Disease Two Risk Factors: Age > 65 Hypertension Diabetes Cholesterol > 240 mg/dl Smoking If patient has a specific contraindication (asthma not COPD) to beta blockers: Clonidine 0.2 mg PO tablet night before surgery Clonidine TTS#2 Patch (0.2 mg/24 hours) night before surgery Clonidine 0.2 mg PO table morning of surgery. Hold for systolic blood pressure less than 120. If Unable to take beta blockers Beta Blockers: Atenolol 25 mg po qd to start, if heart rate greater than 60 and systolic blood pressure greater than 120 mmHg. Titrate dose to effect. Atenolol or Metoprolol IV on day of surgery. Atenolol or Metoprolol IV post op until taking PO then. Atenolol 100 mg PO qd for at least a week post op (hold for heart rate less than 55 or systolic blood pressure less than 100 mmHg) If known CAD or PVD continue beta blocker indefinitely.

63. Summary Long Term Implications Long Term Implications Spectrum of Injury Spectrum of Injury Aggressive Therapy Aggressive Therapy Education Prevention