β-Blockers and Cardiac Events in Noncardiac Surgery Lessons from DECREASE-IV

M Chadi Alraies, MD Department of Hospital Medicine Grand Round Cleveland Clinic Foundation

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Agenda
• • • • Perioperative cardiac events RCRI ACC/AHA Guidelines for perioperative BB use. What is already known about perioperative βblockers • Literature review • DECREASE-IV study
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Introduction
• About 20 million Americans undergo surgery with general anesthesia each year.1 • Cardiac events (MI or Cardiac death) result in perioperative mortality rate of 3-6%

1. July 20, 2005 Los Angeles Times

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Incidence of Perioperative Myocardial Infarction After Noncardiac Surgery
Goldman et al. NEJM 1977 Mangano et al. NEJM 1990 Shah et al. Anesth Analg 1990 Ashton et al., Ann Intern Med 1993 Mangano et al., NEJM 1995 Deveraux et al., CMAJ 2005 5.8% 3.0% perioperative MI 4.7-5.6% in patients with known coronary disease 1.8% perioperative MI in men over the age of 40 1.4%, 3.2%, to 6.9% in successive surgical patients ~3%
non-fatal MI in POISE trial in the placebo group was 5.1% at 30 days.

Deveraux et al., Lancet 2008

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Perioperative cardiac events
• The most common reason for preoperative evaluation. • Associated with increased mortality and results in higher costs

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Prognosis of perioperative MI after noncardiac surgery

• 15-25% in-hospital mortality, of which perioperative MI accounts for 2/3 • Nonfatal perioperative MI predisposes to death, ACS, or progressive angina:
– Post-op troponin I > 1.5 mcg/L: increased 6-mo mortality (OR 5.9) – Post-op troponin I > 0.6 mcg/L: increased 32-mo mortality (OR 2.15)

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Pathophysiology of Perioperative MI
• Multifactorial • Myocardial oxygen demand/supply mismatch due to:
– Perioperative surgical stress – Tachycardia – Hypertension – Pain

• Coronary plaque instability and subsequent rupture also lead to infarction.
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ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery

ACC/AHA Guideline JACC 2007;50:159-241

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Revised Cardiac Risk Index (RCRI)
Five independent predictors of major cardiac complications* History of ischemic heart disease History of compensated or prior HF History of cerebrovascular disease Diabetes mellitus requiring treatment with insulin Preoperative serum creatinine >2.0 mg/dL (177 mol/L) Rate of cardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest according to the number of predictors ¥ No risk factors - 0.4 percent (95% CI 0.1-0.8 percent) One risk factor - 1.0 percent (95% CI 0.5-1.4 percent Two risk factors - 2.4 percent (95% CI 1.3-3.5 percent Three or more risk factors - 5.4 percent (95% CI 2.8-7.9 percent)

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Applying Classification of Recommendations and Level of Evidence
Level A Class I Class IIa Class IIb • Recommendation’s usefulness/ efficacy less well established • Greater conflicting evidence from multiple randomized trials or meta-analyses Class III • Recommendation that procedure or treatment not useful/effective and may be harmful • Sufficient evidence from multiple randomized trials or meta-analyses

Multiple (3-5) population risk strata evaluated
Level B

Limited (2-3) population risk strata evaluated
Level C

• Recommen• Recommendation that dation in favor of procedure or treatment or treatment is procedure being useful/ effective useful/ effective • Sufficient • Some conflicting evidence from evidence from multiple multiple randomized trials randomized trials or meta-analyses or meta-analyses

Very limited (1-2) population risk strata evaluated
Class I Class IIa Class IIb Class III

Benefit >>> Risk

What it means

Benefit >> Risk Additional studies with focused objectives needed
IT IS REASONABLE to perform procedure/ administer M C Alraies

Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful
MAY BE CONSIDERED

Risk ≥ Benefit No additional studies needed

SHOULD be performed/ administered

SHOULD NOT NOT HELPFUL 11 MAY BE HARMFUL

ACC/AHA Recommendation for Beta Blockers
• Class I – Patients on BB should remain on these agents [level C] – BB should be given to patients undergoing vascular surgery who are at high cardiac risk owing to the finding of ischemia on preop testing [level B] Class IIa – BB probably recommend those undergoing vascular surgery preop testing notes CHD [level B] – BB probably recommend high cardiac risk with more than 1 clinical risk factor [level B] – BB probably recommend preop assessment identifies CHD or high cardiac risk with > 1 risk factor and undergoing intermediate risk surgery or vascular surgery [level B] Class IIb – BB uncertain in patient with a single risk factor undergoing intermediate or vascular surgery [level C] – BB uncertain in patient with no risk factors undergoing vascular surgery [level B] Class III – Beta blockers should not be given to patients undergoing surgery who have absolute contraindications to beta blockade. [level C]
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ACC/AHA Guideline JACC 2007;50:159-241

ACC/AHA Recommendation for Beta Blockers

ACC/AHA Guideline JACC 2007;50:159-241

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ACC/AHA guidelines Recommendations for Statin Therapy
CLASS I • For patients currently taking statins and scheduled for noncardiac surgery, statins should be continued. (B) CLASS IIa • For patients undergoing vascular surgery with or without clinical risk factors, statin use is reasonable. (B) CLASS IIb • For patients with at least 1 clinical risk factor who are undergoing intermediate-risk procedures, statins may be considered. (C)
ACC/AHA Guideline JACC 2007;50:159-241 M C Alraies 14

Perioperative β-Blockers

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Mechanism of Beta-blockers?
• Decrease myocardial oxygen demand
– Heart rate – Myocardial contractility

• • • •

Reduce the adrenergic activity Reduce levels of free fatty acid Increase myocardial glucose uptake Coronary plaque stability – requires weeks
– Anti-inflammatory – Progression of atherosclerosis
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● Most trials are inadequately powered. ● Few randomized trials of medical therapy to prevent perioperative MACE have been performed. ● Few randomized trials have examined the role of perioperative beta-blocker therapy, and there is particularly a lack of trials that focus on high-risk patients. ● Studies to determine the role of beta blockers in intermediate- and low-risk populations are lacking. ● Studies to determine the optimal type of beta blockers are lacking. ● No studies have addressed care-delivery mechanisms in the perioperative setting, identifying how, when, and by whom perioperative beta-blocker therapy should be implemented and monitored.
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Review of literature

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Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery. Mangano 1996

Participants Surgery Intervention Administration Median follow-up

200 patients. Elective non-cardiac surgery Atenolol (100mg PO or 10 IV) vs. placebo Before anesthesia & Immediately after surgery for 7 days 24 months

Primary outcome

composite all-cause mortality, MI, UA, CHF

Mangano DT, Layug EL, Wallace A, et al; for Multicenter Study of Perioperative Ischemia Research Group. Effect of atenolol on mortality and M C Alraies 19 cardiovascular morbidity after noncardiac surgery. N Engl J Med. 1996;335:1713–1720.

Mangano 1996
83% 68%

P = 0.008

Overall Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol and Placebo Groups Who Survived to Hospital Discharge.
Mangano DT. N Engl J Med. 1996;335:1713–1720.

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Mangano 1996
90% 79%

Event-free Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol and Placebo Groups Who Survived to Hospital Discharge. N Engl J Med. 1996;335:1713–1720.
Mangano DT, N Engl J Med. 1996;335:1713–1720.

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Mangano 1996
• In patients who have or are at risk for CAD + noncardiac surgery, treatment with atenolol reduce mortality and the incidence of MACE for two years after surgery.

Mangano DT, N Engl J Med. 1996;335:1713–1720.

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The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery Poldermans D 1999
Participants Stress test Surgery Intervention 112 patients. Positive dobutamine echocardiography Elective non-cardiac surgery Bisoprolol (5 mg titrated to 10mg) vs. placebo

Administration Dose titration
Median follow-up Primary outcome

Daily for 1 week before surgery and QD for 30 days post surgery. Yes (1 week interval)
24 months composite all-cause mortality, MI, UA, CHF

Poldermans D, Boersma E, Bax JJ, et al; for Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med. 1999;341: 1789–1794.

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Poldermans D,1999

Kaplan–Meier Estimates of the Cumulative Percentages of Patients Who Died of Cardiac Causes or Had a Nonfatal Myocardial Infarction during the Perioperative Period.
Poldermans D,. N Engl J Med. 1999;341: 1789–1794.

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Poldermans D,1999

Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction in high-risk patients who are undergoing major vascular surgery.

Poldermans D,. N Engl J Med. 1999;341: 1789–1794.

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β-Blockers and Reduction of Cardiac Events in Noncardiac Surgery, scientific review. Auerbach 2002

Auerbach AD, Goldman L. Beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA. 2002;287:1435–1444

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1. β-blockers work the best in high risk patients. 2. Need more studies for patients with stable coronary disease and are undergoing elective surgery? 3. What is the optimal duration of therapy? 4. Which agent is the best? 5. When to start BB therapy?

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Auerbach AD. JAMA. 2002;287:1435–144427

Perioperative -blockade (POBBLE) for patients undergoing infrarenal vascular surgery: Results of a randomized double-blind controlled trial. Brady et al 2005, UK

Participants Surgery

103 patients – median age 73 yrs Infrarenal vascular surgery

Intervention
Administration Dose titration Median follow-up Primary outcome

Metoprolol (50 mg BID) vs. Placebo
Day before surgery twice daily & Continued for 7-14 days

No 30 days composite all-cause mortality, MI, UA, CHF

Brady AR, Gibbs JS, Greenhalgh RM, et al. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. 2005;41:602– 609.

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POBBLE trial 2005
• lower-risk vascular surgical patients, perioperative β-blockade does not reduce 30day cardiovascular morbidity and mortality but, facilitate earlier patient discharge.

Brady AR. J Vasc Surg. 2005;41:602– 609.

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The effects of perioperative betablockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Yang et al 2006

Participants Surgery Intervention Administration Dose titration

500 vascular patients – mean age 66 yrs Vascular surgery only Metoprolol (50-100mg) vs. placebo 2 hours before anesthesia induction then daily for 5 days. No

Median follow-up
Primary outcome

30 days and 6 months
composite all-cause mortality, MI, UA, CHF

Yang H, Raymer K, Butler R, et al. The effects of perioperative betablockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. 2006;152:983–990 30

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Outcomes at 30 days postoperative

Yang H. Am Heart J. 2006;152:983–990

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Cumulative risk primary outcomes at 6 months.

Yang H. Am Heart J. 2006;152:983–990

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MaVS trial 2006

• Metoprolol has no effect in reducing the cardiac event rate in vascular patients at 30 days postoperative or at 6 months.

Yang H. Am Heart J. 2006;152:983–990

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Pooled RRR of all four trials

Yang H. Am Heart J. 2006;152:983–990

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Effect of perioperative blockade in patients with diabetes undergoing major non-cardiac surgery: randomized placebo controlled, blinded multicentre (DIPOM) trial
Participants Surgery Mean age Intervention 921 diabetic patients. Major (over 1 hr) non-cardiac surgery (majority orthopedic) 64 yrs Metoprolol XL 50 mg day before surgery Metoprolol XL 100 mg 2 hours before induction, then Metoprolol XL 100 mg daily x 8 days. Day of surgery for 8 days post op No 18 months composite all-cause mortality, MI, UA, CHF Followed Mangano’s inclusion criteria and protocol. (2.5 x bigger sample size)
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Administration Titration of therapy Median follow-up Primary outcome Comment

Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomized placebo controlled, blinded multicentre trial. BMJ. 2006;332:1482.

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Kaplan-Meier plot of time to primary outcome measure

Juul AB. DIPOM. BMJ. 2006;332:1482.

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Diabetic Postoperative Mortality and Morbidity (DIPOM) 2006 • Heart rate lower with metoprolol (72 vs 78 bpm) • Primary outcome: 21% metoprolol group vs. 20% placebo group • Metoprolol XL (100 mg a day for up to eight perioperative days) for diabetics does not affect long term mortality and cardiac morbidity. (But wide CI)
Juul AB. DIPOM. BMJ. 2006;332:1482.

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Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial)

Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomized controlled trial. Lancet. 2008;371:1839 –1847.

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PeriOperative Ischemia Evaluation (POISE)
Participants 8351 patients. Hx: CAD, PVD, CVA, CHF within 3 yrs of surgery, or vascular surgery

Surgery
Mean age

Major non-cardiac surgery – majority vascular surgeries
69 yrs Metoprolol XL 100 mg 2-4 hours before induction Metoprolol XL 100 mg 0-6 hours after surgery Metoprolol XL 200 mg daily for 30 days following surgery Metoprolol 15mg IV every 6 hours if NPO Day of surgery & for 8 days post op 18 months No composite all-cause mortality, MI, UA, CHF 75 centers, 9 countries Goal 10000 patients (final enrollment 8351)
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Intervention

Administration Median follow-up Titration of therapy Primary outcome Comment

Devereaux PJ, (POISE trial). Lancet. 2008;371:1839 –1847.

Effects of study treatment on primary and secondary outcomes at 30 days
8351 Patients Hx: CAD, PVD, CVA, CHF Major vascular surgery

4174 Patients
Metoprolol XL 100mg 2-4 hours before surgery and 200mg/day for 30 days

4177 Patients Placebo

Cardiovascular death, nonfatal myocardial infarction, or non-fatal cardiac arrest 5.8%

Cardiovascular death, nonfatal myocardial infarction, or non-fatal cardiac arrest 6.9%

Total mortality 3.1%

Total mortality 2.3%

Stroke 1% Non-fatal stroke 0.6%
Devereaux PJ,. Lancet. 2008;371:1839 –1847.

Stroke 0.5% Non-fatal stroke 0.3%
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Kaplan-Meier estimates of the primary outcome (A), myocardial infarction (B), stroke (C), and death (D)

Primary

MIs

Primary

MIs

Strokes

Death

Strokes

Death

Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.

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PeriOperative Ischemia Evaluation (POISE)

BB prevents 15 MI 3 Revasc 7 Atrial Fib

BB causes: 8 Deaths 5 Stroke (1.0% vs. 0.5%, HR 2.17, p = 0.005) 53 Hypotension (15.0% vs. 9.7%, p < 0.0001) 42 Bradycardia (6.6% vs. 2.4%, p < 0.0001)
Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.

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POISE observations
• BB decreased non-fatal MI and CV mortality • Evidence does not support initiation of BB in most pts undergoing surgery with (RCRI <3) • Benefit of BB for:
– High risk patients (RCRI 3+) – Pts with evidence of ischemia by stress testing

• However, most patients at highest CV risk have independent indications for B-B therapy
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POISE limitations
• Significant hypotension more often in BB group (15% vs. 9.7%) • Fixed dose, not titrated • Started treatment only 2-4 hrs prior to surgery • High starting dose of oral metoprolol may have contributed to hypotension/stroke rate.

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Bisoprolol and Fluvastatin for the Reduction of Perioperative Cardiac Mortality and Myocardial Infarction in Intermediate-Risk Patients Undergoing Noncardiovascular Surgery A Randomized Controlled Trial (DECREASE-IV)
Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AW, van Poorten F, Bax JJ, Thomson IR, Poldermans D; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Departments of Vascular Surgery, Erasmus Medical Centre, Rotterdam, the Netherlands. Annals of Surgery. 2009 Jun;249(6):921-6.

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Objective
• This study evaluated the beta-blockers and statins for the prevention of perioperative cardiovascular events in intermediate-risk patients undergoing noncardiovascular surgery.

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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DECREASE-IV
Participants Surgery Mean age 1066 patients. Risk for a perioperative MACE 1-6% (RCRI 2-3) elective noncardiovascular surgery 65 yrs Bisoprolol starting at 2.5 mg po daily Dose modified by 1.25 or 2.5 mg per day Maximum dose of 10 mg po dialy Metoprolol IV every 6 hours if NPO Fluvastatin XL 80 mg po daily (NGT if unable to swallow) Median 34 days before surgery & 30 days after surgery

Intervention

Administration

Median follow-up
Titration of therapy Primary end point

30 days
Yes (Target: heart rate of 50-70 bpm) Cardiac death, all-cause mortality, non-fatal MI
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Secondary end point Cardiac arrhythmias, Acute heart failure, Coronary revascularization
Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Methods
• • • • • A prospective Open-label 2 x 2 factorial design Multicenter Randomized Controlled trial

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Safety End Points
• Stroke • Significant bradycardia & hypotension • Significant liver and muscles markers
– ALT 3 times upper limit of normal – CK level more than 10 times upper limit of normal – Myopathy – Rhabdomyolysis

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Incidence of primary study end point by treatment group

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

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Limitations
• Majority of patients (RCRI 2-3) had an independent indication for beta-blockade prior to surgery • Early termination for slow recruitment
– 78% of the patient who met the inclusion criteria were already on beta-blockers and/or statin

• Only 1% of the study population were actually titrated. • Not blinded: Beta-blocker therapy cannot be titrated to heart rate
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POISE
Type of BB Starting dose Initiation time Dose titration Metoprolol XL 100 mg 2 hours preop Then 200 mg daily 1 day No

DECREASE - IV
Bisoprolol 2.5 mg daily 30 days Preop Titrated to 10 mg po daily 30 days Yes (only in 1%)

Dose adjustment for HR
Withdrawal of therapy Sample size Age (mean) Type of surgery

No
Early (7 days) 8351 69 yrs Non-cardiac
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yes
Late (30 days) 1066 65 yrs Non-cardiovascular
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Thank you
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Questions

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