Perioperative Medical Therapy: Beta Blockers, Statins, ACE-Inhibitors, ARB Effects on Mortality Art Wallace, MD, PhD SF VAMC Chief of Anethesia and Vice Chair of Anesthesia and Perioperative Care UCSF Disclosures No financial interests to disclose. Worked in field for many years and have opinions. 1
Goals & Objectives: How should you do a preop assessment in 2015? Does perioperative beta blockade reduce risk? What does CARP say? What about Poldermans? What about statins? What about PCI, Aspirin, Plavix? What about the POISE Data? What do I do now? 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Fleisher, LA, et. al. I know you memorized all 54 pages. ECHO: Patients with clinically suspected moderate or greater degrees of valvular stenosis or regurgitation undergo preoperative echocardiography if there has been either 1) no prior echocardiography within 1 year or 2) a significant change in clinical status or physical examination since last evaluation. (Class 1) Monitor patients with severe AS, MR, AR, MR (Class 2A) ECG for Known CAD (Class 2) ECHO for CHF without prior evaluation or change in condition (Class 2) Stress Test: In elevated risk patients only if it will change management. Coronary angiography: Not recommended (Class 3) CABG prior to non-cardiac surgery: Not recommended (Class 3) PCI with DES: Delay non-cardiac surgery 365 days PCI with BMS: Delay 30 days, Balloon 14 days. 2
Recommendations for Beta-Blocker Medical Therapy Beta blockers should be continued in patients undergoing surgery who have been on beta blockers chronically. (I) ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery Recommendations for Beta-Blocker Medical Therapy It is reasonable for the management of beta blockers after surgery to be guided by clinical circumstances, independent of when the agent was started. (IIa) Beta blockers are probably recommended for patients in whom preoperative assessment for vascular surgery identifies high cardiac risk, as defined by the presence of more than 1 clinical risk factor. (IIb) Beta blockers are probably recommended for patients in whom preoperative assessment identifies coronary heart disease or high cardiac risk as defined by the presence of more than 1 clincial risk factor, who are undergoing intermediate risk or vascular surgery. (IIb) ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery 3
Recommendations for Beta-Blocker Medical Therapy It is reasonable for the management of beta blockers after surgery to be guided by clinical circumstances, independent of when the agent was started. (IIa) In patients with intermediate- or high-risk myocardial ischemia noted in preoperative risk stratification tests, it may be reasonable to begin perioperative beta blockers. (IIb) In patients with 3 or more RCRI risk factors (e.g., diabetes mellitus, HF, coronary artery disease, renal insufficiency, cerebrovascular accident), it may be reasonable to begin beta blockers before surgery. (IIb) In patients with a compelling long-term indication for beta-blocker therapy but no other RCRI risk factors, initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit. In patients in whom beta-blocker therapy is initiated, it may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably more than 1 day before surgery. (IIb) Beta-blocker therapy should not be started on the day of surgery. (III) ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery Recommendations for Statin Therapy Statins should be continued in patients currently taking statins and scheduled for noncardiac surgery. (I) Perioperative initiation of statin use is reasonable in patients undergoing vascular surgery. (IIa) Perioperative initiation of statins may be considered in patients with clinical indications according to GDMT who are undergoing elevated-risk procedures. (IIb) ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery 4
Recommendations for Alpha-2 Agonists Class III (Changed) Alpha-2 agonists for prevention of cardiac events are not recommended in patients who are undergoing noncardiac surgery. ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery ACE-I and ARB Continuation of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers perioperatively is reasonable.(iia) If angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers are held before surgery, it is reasonable to restart as soon as clinically feasible postoperatively. (IIa) ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery 5
Anti-Platelet Agents Continue Dual Anti-Platelet Therapy (DAPT) in patients undergoing urgent non-cardiac surgery during the first 4-6 weeks after BMS or DES implantation, unless the risks of bleeding outweighs the benefit of stent thrombosis prevention. In patients where surgery requires discontinuation of P2Y inhibitors, continue aspirin and restart P2Y platelet inhibitor as soon as possible. In patients undergoing nonemergency/nonurgent non-cardiac surgery without prior coronary stenting, it may be reasonable to continue aspirin when the risk of CAD outweighs risk of bleeding. Initiation of ASA is not beneficial in patients undergoing elective noncardiac surgery who have not had previous coronary stenting. ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery CARP TRIAL (McFalls Coronary Artery Revascularization Prophylaxis Trial. et al. N Engl J Med. 2004 ) Multi-centered, randomized, prospective, controlled trial sponsored by the Department of Veterans Affairs. Patients with significant CAD who are undergoing operations for peripheral arterial disease are randomized to myocardial revascularization versus best medical care Can 3.2 + 1.5 < 3.0? NO 6
Overall Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol and Placebo Groups who Survived to Hospital Discharge. 6 month survival 100% vs 92% p < 0.001, 1 year survival 97% vs 86% p =0.005, 2 year survival 90% vs 79% p=0.019, Mangano et. al. NEJM 335:23: 1713-1720, 1996. Kaplan-Meir Estimate of Cumulative Percentage of Patients who Died of Cardiac Causes or had a Non Fatal Myocardial Infarction during the Perioperative Period Poldermans et. al. NEJM 341:24:1789-1840, 1999. 7
Wallace A.W., et. al. Effect of Clonidine on Cardiovascular Morbidity and Mortality after Non-Cardiac Surgery Anesthesiology 101(2) 284-293, 2004 1.0 0.9 Clonidine 0.8 Su r vi val 0.7 0.6 0.5 0.4 0.3 Placebo 0.2 0.1 0.0 0 200 400 600 Days after Surgery Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leão P, Prospective, randomized, placebo-controlled, doubleblind clinical trial was performed to analyze the effect of atorvastatin compared with placebo on the occurrence of a 6-month composite of cardiovascular events after vascular surgery. Cardiovascular complications are the most important cause of perioperative morbidity and mortality among patients undergoing vascular surgery. Statin therapy may reduce perioperative cardiac events through stabilization of coronary plaques. METHODS: One hundred patients were randomly assigned to receive 20 mg atorvastatin or placebo once a day for 45 days, irrespective of their serum cholesterol concentration. Vascular surgery was performed on average 30 days after randomization, and patients were prospectively followed up over 6 months. The cardiovascular events studied were death from cardiac cause, nonfatal myocardial infarction, unstable angina, and stroke. RESULTS: Fifty patients received atorvastatin, and 50 received placebo. During the 6-month follow-up primary end points occurred in 17 patients, 4 in the atorvastatin group and 13 in the placebo group. The incidence of cardiac events was more than three times higher with placebo (26.0%) compared with atorvastatin (8.0%; P =0.031). The risk for an event was compared between the groups with the Kaplan-Meier method, as event-free survival after vascular surgery. Patients given atorvastatin exhibited a significant decrease in the rate of cardiac events, compared with the placebo group, within 6 months after vascular surgery (P =0.018). Caramelli B. J Vasc Surg. 2004 May;39(5):967-75 8
Fluvastatin and Perioperative Events in Patients Undergoing Vascular Surgery Olaf Schouten, M.D., Ph.D., Eric Boersma, Ph.D., Sanne E. Hoeks, M.Sc., Robbert Benner, Ph.D., Hero van Urk, M.D., Ph.D., Marc R.H.M. van Sambeek, M.D., Ph.D., Hence J.M. Verhagen, M.D., Ph.D., Nisar A. Khan, Ph.D., Martin Dunkelgrun, M.D., Ph.D., Jeroen J. Bax, M.D., Ph.D., Don Poldermans, M.D., Ph.D., for the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group NEJM Volume 361:980-989, 2009 Background Adverse cardiac events are common after vascular surgery. We hypothesized that perioperative statin therapy would improve postoperative outcomes. Methods In this double-blind, placebo-controlled trial, we randomly assigned patients who had not previously been treated with a statin to receive, in addition to a beta-blocker, either 80 mg of extended-release fluvastatin or placebo once daily before undergoing vascular surgery. Lipid, interleukin-6, and C-reactive protein levels were measured at the time of randomization and before surgery. The primary end point was the occurrence of myocardial ischemia, defined as transient electrocardiographic abnormalities, release of troponin T, or both, within 30 days after surgery. The secondary end point was the composite of death from cardiovascular causes and myocardial infarction. Results A total of 250 patients were assigned to fluvastatin, and 247 to placebo, a median of 37 days before vascular surgery. Levels of total cholesterol, low-density lipoprotein cholesterol, interleukin-6, and C-reactive protein were significantly decreased in the fluvastatin group but were unchanged in the placebo group. Postoperative myocardial ischemia occurred in 27 patients (10.8%) in the fluvastatin group and in 47 (19.0%) in the placebo group (hazard ratio, 0.55; 95% confidence interval [CI], 0.34 to 0.88; P=0.01). Death from cardiovascular causes or myocardial infarction occurred in 12 patients (4.8%) in the fluvastatin group and 25 patients (10.1%) in the placebo group (hazard ratio, 0.47; 95% CI, 0.24 to 0.94; P=0.03). Fluvastatin therapy was not associated with a significant increase in the rate of adverse events. Conclusions In patients undergoing vascular surgery, perioperative fluvastatin therapy was associated with an improvement in postoperative cardiac outcome. (Current Controlled Trials number, ISRCTN83738615 Major Problem Don Poldermans misconduct report finds lack of patient consent, sloppy data collection, and data fabrication 9
POISE : Perioperative Ischemic Evaluation (POISE Study Group Lancet 2008) Significant hypotension (15.0% vs. 9.7%, p < 0.0001) Significant bradycardia (6.6% vs. 2.4%, p < 0.0001). Total mortality was increased in the metoprolol group (3.1% vs. 2.3%, HR 1.33, p = 0.03) Stroke (1.0% vs. 0.5%, HR 2.17, p = 0.005). What do you do with these results? Metoprolol XL 400 mg PO DOS is 16 times the recommended starting dose in the PDR. 32 times the dose for patients with CHF. 4 times the MAXIMAL recommended starting dose Should we ignore these results as an obvious result of excessive beta blocker administration? Aspirin in patients undergoing noncardiac surgery. Devereaux et. al. N Engl J Med. 2014 Apr 17;370(16):1494-503. Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. 10,010 patients for non-cardiac surgery at risk for vascular complications ASA vs Placebo, Clonidine vs Placebo. 5628 Not on ASA, 4382 On ASA ASA 100 mg for 30 days. 7.1% outcome (7% ASA, 7.1% Non) 4.6% bleeding ASA 3.5% Non, HR 1.23, CI 1.01-1.49, P=0.04 10
Kaplan Meier Estimates of the Primary Composite Outcome of Death or Nonfatal Myocardial Infarction at 30 Days. Devereaux P et al. N Engl J Med 2014;370:1494-1503. Clonidine in patients undergoing noncardiac surgery. Devereaux PJ et. al. N Engl J Med. 2014 Clonidine, as compared with placebo, did not reduce the number of primaryoutcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02). Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. 11
Kaplan Meier Estimates of the Primary Outcome, According to Study Group. Devereaux P et al. N Engl J Med 2014;370:1504-1513. Perioperative Beta Blocker Use in the 38,779 operations performed at the SF-VAMC between 1996 and 2008 (Wallace Anes 2010) 12
What about ACE-Inhibitors in Non-Cardiac? Mudumbai,Takemoto, Wallace 2014 Perioperative Withdrawal of ACE-I increases mortality 2.9 fold. Association between Withholding Angiotensin Receptor Blockers in the Early Postoperative Period and 30-day Mortality: A Cohort Study of the Veterans Affairs Healthcare System Anesthesiology 8 2015, Vol.123, 288-306. 13
Caveats Avoid Tachycardia Avoid Hypotension Avoid Hypertension Avoid Myocardial Ischemia Avoid Medication Withdrawal. Hypotension %Mortality 25% 20% 15% 10% 5% Mortality Day 2 Mortality Day 30 Mortality 1 year diastolic<30 11% <40 28% mean<40 8% <50 16% <55 89% systolic<60 12% <80 34% <90 55% 0% 0 10 20 30 0 10 20 30 0 10 20 30 Duration of Hypotension in minutes Blue <=15% of patients had hypotension Circle systolic blood pressure Purple 16 24% of patients had hypotension Triangle Mean arterial pressure Orange 25 50% of patients had hypotension Diamond diastolic blood pressure Yellow >50% of patients had hypotension 14
Hypertension Mortality Day 2 Mortality Day 30 Mortality 1 year %Mortality 10.0% 8.0% 6.0% 4.0% diastolic>120 16% >100 35% >90 55% mean>130 33% >110 71% Systolic>200 16% >160 58% 2.0% 0.0% 0 10 20 30 0 10 20 30 0 10 20 30 Duration of Hypertension in minutes Blue <=16% of patients had hypertension Circle systolic blood pressure Orange 17 50% of patients had hypertension Triangle Mean arterial pressure Yellow >50% of patients had hypertension Diamond diastolic blood pressure Tachycardia 10.0% 8.0% Mortality Day 2 Mortality Day 30 Mortality 1 year >120 8% >100 29% %Mortality 6.0% 4.0% 2.0% No Tachycardia 0.0% 0 10 20 30 0 10 20 30 0 10 20 30 Duration of tachycardia in minutes Blue <10% of patients had tachycardia Heart rate >120/minute Orange 11 30% of patients had tachycardia Heart rate >100/minute 15
Summary: Follow the standard rules for work up of medical disease. Do not use the perioperative period to order special tests. Use the standard rules and doses for medications. If a patient needs a medication preop, they likely need it post op. Be careful avoid tachycardia, hypotension, hypertension. Do not withdraw medications. CAD, PVD, or significant risk factors for CAD beta blocker CAD, PVD, or risk statin CAD, PVD, or PCI ASA 16