9/21/2015

1

Perioperative Medical Therapy: Beta Blockers,

Statins, ACE-Inhibitors, ARB – Effects on Mortality

Art Wallace, MD, PhDSF 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.

9/21/2015

2

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 PerioperativeCardiovascular 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.

9/21/2015

3

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 clincialrisk factor, who are undergoing intermediate risk or vascular surgery. (IIb)

ACC/AHA 2014 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery

9/21/2015

4

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 noncardiacsurgery. (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

9/21/2015

5

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

9/21/2015

6

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 et al. N Engl J Med. 2004 )

Coronary Artery Revascularization Prophylaxis Trial.

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

9/21/2015

7

Overall Survival in the Two Years after Noncardiac Surgery among 192 Patients in theAtenolol 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.

9/21/2015

8

Wallace A.W., et. al. Effect of Clonidine on Cardiovascular Morbidity and Mortality after Non-Cardiac Surgery Anesthesiology 101(2) 284-

293, 2004

Days after Surgery0 200 400 600

Surv

ival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Clonidine

Placebo

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,

Caramelli B. J Vasc Surg. 2004 May;39(5):967-75

Prospective, randomized, placebo-controlled, double-blind 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).

9/21/2015

9

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 vascularsurgery. We hypothesized that perioperative statin therapy wouldimprove 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, perioperativefluvastatin therapy was associated with an improvement in postoperative cardiac outcome. (Current Controlled Trials number, ISRCTN83738615

Major ProblemDon Poldermans misconduct report finds lack of patient consent, sloppy data collection, and data fabrication

9/21/2015

10

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

9/21/2015

11

Devereaux P et al. N Engl J Med 2014;370:1494-1503.

Kaplan–Meier Estimates of the Primary Composite Outcome of Death or Nonfatal Myocardial Infarction at 30 Days.

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 primary-outcome 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 noncardiacsurgery 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.

9/21/2015

12

Devereaux P et al. N Engl J Med 2014;370:1504-1513.

Kaplan–Meier Estimates of the Primary Outcome, According to Study Group.

Perioperative Beta Blocker Use in the 38,779 operations performed at the

SF-VAMC between 1996 and 2008 (Wallace Anes 2010)

9/21/2015

13

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.

9/21/2015

14

Caveats

Avoid Tachycardia

Avoid Hypotension

Avoid Hypertension

Avoid Myocardial Ischemia

Avoid Medication Withdrawal.

Hypotension

0%

5%

10%

15%

20%

25%

0 10 20 30

diastolic<30‐11%

<40‐28%

mean<40‐8%

<50‐16%

<55‐89%

systolic<60‐12%

<80‐34%

<90‐55%

0 10 20 30 0 10 20 30

%Mortality

Duration of Hypotension in minutes

Mortality Day 2 Mortality Day 30 Mortality 1 year

Blue <=15% of patients had hypotensionCircle systolic blood pressure

Orange 25‐50% of patients had hypotensionDiamond diastolic blood pressure

Purple 16‐24% of patients had hypotensionTriangle Mean arterial pressure Yellow >50% of patients had hypotension

9/21/2015

15

Hypertension%Mortality

Duration of Hypertension in minutes

Mortality Day 2 Mortality Day 30 Mortality 1 year

Blue <=16% of patients had hypertensionCircle systolic blood pressure

Yellow >50% of patients had hypertensionDiamond diastolic blood pressure

Orange 17‐50% of patients had hypertensionTriangle Mean arterial pressure

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

0 10 20 30

diastolic>120‐16%

>100‐35%

>90‐55%

mean>130‐33%

>110‐71%

Systolic>200‐16%

>160‐58%

0 10 20 30 0 10 20 30

Tachycardia

%Mortality

Duration of tachycardia in minutes

Mortality Day 2 Mortality Day 30 Mortality 1 year

Blue <10% of patients had tachycardiaHeart rate >120/minute

Orange 11‐30% of patients had tachycardiaHeart rate >100/minute

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

0 10 20 30

>120‐8%

>100‐29%

0 10 20 30 0 10 20 30

No Tachycardia

9/21/2015

16

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