Clinical trial NCT01837069
Conditions: Osteoarthritis Cardiovascular Disease
Keywords: Hypertension Diabetes Coronary Artery Disease Peripheral Vascular Disease
Sponsor: NYU Langone Health
Start date: 2014-02-01; Completion date: 2018-04-02
Enrollment: 198 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is designed to determine the best preoperative management strategy for patients undergoing orthopedic surgery.

Detailed description:
OPTIMIZE - OS (Optimization of Pre-surgical Testing with an Intensive Multifactorial Intervention to MinimiZe Cardiovascular Events - Orthopedic Surgery) trial is to determine the best management strategy for patients undergoing orthopedic surgery. OPTIMIZE will be a prospective randomized trial that will enroll patients during pre-surgical testing before orthopedic surgery. This trial will investigate different strategies aimed at lowering cardiovascular events following orthopedic surgery. The study will compare an intensive multifactorial intervention comprising behavioral modification and polypharmacologic therapy aimed at several modifiable risk factors versus usual care. The trial hypothesis is that a personalized optimization approach is superior to usual care in reducing a composite of death, myocardial infarction, stroke, transient ischemic attack, myocardial necrosis, venous thromboembolism or thrombosis requiring reoperation at 30-days. Secondary endpoints include length of stay, major bleeding, each individual endpoint from the primary endpoint, and quality of life.

Arms: arm 1: Lifestyle counseling (nutrition, physical activity, medication compliance and smoking cessation) Atorvastatin 80mg PO QD Metoprolol 25mg PO BID if HR is elevated Lisinopril 2.5 mg PO QD if SBP is elevated arm 2: Standard of care
Interventions: intervention 1: Metoprolol intervention 2: Lisinopril intervention 3: Atorvastatin intervention 4: Lifestyle counseling
Intervention descriptions: intervention 1: 25mg PO BID if the HR is elevated at preadmission testing intervention 2: 2.5mg PO QD if the HR is elevated at preadmission testing intervention 3: 80mg PO QD at preadmission testing intervention 4: Diet, exercise, medication adherance and smoking counseling

Protocol documents:
Prot_SAP_000.pdf: 
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Risk Factor Control before 
Orthopedic Surgery 
OPTIMIZE – OS Trial
Study Principal Investigator
Jeffrey S. Berger, MD, MS, FAHA, FACC
Assistant Professor of Medicine and Surgery
Director of Cardiovascular Thrombosis
New York University School of Medicine
530 First Avenue, Skirball 9R
New York, NY 10016
Tel. 212-263-4004
Fax. 212-263-3988
E-mail. jeffrey.berger@nyumc.org
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With the increasing longevity of the US population, orthopedic surgery is commonly being 
performed. Although orthopedic surgery has a tremendous benefit improving patient morbidity 
and quality of life, adverse cardiovascular events in the perioperative period are a major 
concern. With this in mind, the objective of OPTIMIZE - OS (Optimization of Pre-surgical 
Testing with an Intensive Multifactorial Intervention to MinimiZe Cardiovascular Events – 
Orthopedic Surgery) trial is to determine the best management strategy for patients 
undergoing orthopedic surgery. OPTIMIZE will be a prospective randomized trial that will enroll 
patients during pre-surgical testing before orthopedic surgery. This trial will investigate different 
strategies aimed at lowering cardiovascular events following orthopedic surgery. The study will 
compare an intensive multifactorial intervention comprising behavioral modification and 
polypharmacologic therapy aimed at several modifiable risk factors versus usual care. The trial 
hypothesis is that a personalized optimization approach is superior to usual care in reducing a 
composite of death, myocardial infarction, stroke, transient ischemic attack, myocardial 
necrosis, venous thromboembolism or thrombosis requiring reoperation at 30-days. Secondary 
endpoints include length of stay, major bleeding, each individual endpoint from the primary 
endpoint, and quality of life. 
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TABLE OF CONTENTS
1.
SPECIFIC AIMS...................................................................................................................5
2.
BACKGROUND AND SIGNIFICANCE ................................................................................6
2.1.
RELEVANT STUDIES
3.
RESEARCH DESIGN AND METHODS...............................................................................8
3.1.
STUDY OBJECTIVES
3.2.
INCLUSION CRITERIA
3.3.
EXCLUSION CRITERIA
3.4.
SCREENING AND RECRUITMENT
3.5.
TIME FRAME
3.6.
INFORMED CONSENT
3.7.
RANDOMIZATION
3.8.
METHODS
3.9.
TABLE 1: STUDY SCHEDULE
3.10.
TREATMENT COMPLIANCE
3.11.
PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
3.12.
CONCOMITANT MEDICATIONS
3.13.
BLOOD TEST
4.
DATA ANALYSIS ...............................................................................................................17
4.1.
SAMPLE SIZE CONSIDERATIONS FOR PRIMARY END-POINT:
4.2.
DATA ANALYSIS PLAN
4.3.
SECONDARY ANALYSES
 
5.
SAFETY MONITORING PLAN...........................................................................................18
5.1.
ATTRIBUTION OF ADVERSE EVENTS
5.2.
PLAN FOR GRADING ADVERSE EVENTS
5.3.
PLAN FOR REPORTING SERIOUS UNANTICIPATED ADVERSE EVENTS
5.4.
PLANS FOR REVISING AND REPORTING NON-SERIOUS ANTICIPATED AND UNANTICIPATED 
ADVERSE EVENTS
6.
REPORTING OF SERIOUS ADVERSE EVENTS .............................................................19
6.1.
PERSONNEL RESPONSIBLE FOR THE SAFETY REVIEW AND IT'S FREQUENCY
7.
POTENTIAL RISKS/PROTECTION AGAINST RISK.........................................................20
7.1.
ALLERGIC REACTIONS
7.2.
HYPOTENSION/BRADYCARDIA
7.3.
MUSCLE DAMAGE
7.4.
BLOOD COLLECTION
8.
POTENTIAL BENEFIT TO THE SUBJECTS .....................................................................21
9. 
DATA MANAGEMENT.......................................................................................................21
10.   
ETHICAL ASPECT OF THE PROPOSED RESEARCH
10.1.
ETHICAL CONDUCT OF THE STUDY
10.2.
CONFIDENTIALITY
11. LITERATURE CITED .........................................................................................................23
12. APPENDICES ...................................................................................................................24
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ABBREVIATIONS 
AE-adverse event 
CRF-Case Report Form 
CAD-coronary artery disease 
DM-diabetes mellitus  
HbA1c -glycosolated hemoglobin A1c 
HDL-C-  High  Density Lipoprotein Cholesterol
hs-CRP-high sensitivity C-reactive protein
IRB-Institutional Review Board 
LDL-low density lipoprotein cholesterol
SAE-Serious Adverse Event
SD-standard deviation 
1. SPECIFIC AIMS
Orthopedic surgery is increasingly being performed in the US population and as the population 
ages; surgery will be performed on older patients with more cardiovascular comorbidities. The 
risk of cardiovascular complications is a major concern during the perioperative period. 
Perioperative cardiovascular events are a major cause of short- and long-term morbidity and 
mortality in subjects undergoing non-cardiac surgery.  Intensive lifestyle and pharmacological 
therapies targeting modifiable risk factors are effective at decreasing cardiovascular events in 
high-risk individuals; however, they remain underused in the perioperative period. Furthermore, 
the effectiveness of an intensive multifactorial approach aimed at minimizing cardiovascular 
events during the perioperative period has not been tested. 
We propose the following aims:

To demonstrate that a short-term intensive multifactorial intervention comprising 
behavioral modification and polypharmacologic therapy aimed at several modifiable risk 
factors in high-risk subjects undergoing orthopedic surgery treatment will decrease 
cardiovascular events in the postoperative period

To demonstrate that a short-term intensive multifactorial intervention comprising 
behavioral modification and polypharmacologic therapy aimed at several modifiable risk 
factors in high-risk subjects undergoing orthopedic surgery treatment will improve the 
subjects risk factor profile prior to surgery

To investigate the relationship between modifiable risk factors (e.g. smoking, blood 
pressure, lipid profile, platelet activity, and inflammatory markers) and cardiovascular 
events in the postoperative period
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The primary hypothesis is that a short-term intensive multifactorial intervention comprising 
behavioral modification and polypharmacologic therapy aimed at several modifiable risk factors 
in high-risk subjects undergoing orthopedic surgery will decrease cardiovascular events in the 
postoperative period
The secondary hypothesis is that a short-term intensive multifactorial intervention comprising 
behavioral modification and polypharmacologic therapy aimed at several modifiable risk factors 
in high-risk subjects undergoing orthopedic surgery will improve the subjects risk factor profile 
prior to surgery
The overall study design can be illustrated in the following figure:
2. BACKGROUND AND SIGNIFICANCE
With the ageing population, more subjects are requiring orthopedic surgery for improvement in 
quality of life.  
Since the presence of clinical comorbidities predisposing to cardiac 
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complications rises with increasing age, an increasing number of surgical procedures in 
patients with cardiac risk factors are to be expected. The risk of cardiovascular complications 
are a major concern for the surgeon and the anesthesiologist during the perioperative period. 
Perioperative 
cardiovascular 
events 
(e.g. 
myocardial 
infarction, 
stroke, 
venous 
thromboembolism) are a major cause of morbidity and mortality and increased length of stay in 
subjects undergoing orthopedic surgery. Non-fatal cardiovascular events during the 
perioperative period predict long-term cardiovascular morbidity and mortality following surgery. 
The catecholamine surge, tachycardia, hypertension, hypercoagulability and increased platelet 
activity associated with surgery may lead to a perioperative cardiovascular event. Another 
potential mechanism of a perioperative cardiovascular event is the rupture of an unstable 
coronary plaque, perhaps because of the systemic inflammatory response to surgery.   
Currently, there is a well known cardiac risk work-up prior to surgery. Nonetheless, many 
subjects are still experiencing adverse perioperative cardiovascular complications. With this in 
mind, the purpose of this study is to investigate whether a short-term intensive multifactorial 
intervention comprising behavioral modification and polypharmacologic therapy aimed at 
several modifiable risk factors is beneficial in high-risk subjects undergoing non-emergent 
orthopedic surgery.
2.1. RELEVANT STUDIES:
Statins are effective in the setting of primary and secondary prevention of cardiovascular 
events in the nonsurgical setting. They represent a class of medicines that are potent lipid 
lowering, anti-inflammatory and plaque stabilizing agents. These beneficial mechanistic 
pleiotropic effects of statins, including inhibition of the inflammatory response, reduced 
thrombosis, enhanced fibrinolysis, decreased platelet reactivity, and improvement of 
microcirculation vasoreactivity, all together culminate in a protective effect that could be readily 
evident in the setting of ischemia–reperfusion injury. in a retrospective cohort study of more 
than 750,000 subjects who underwent noncardiac surgery, Lindenauer and colleagues 
observed that statin therapy is associated with a reduced risk of postoperative death. In a 
randomized trial in subjects undergoing vascular surgery, use of statins were able to lower 
myocardial ischemia and mortality in following vascular surgery independent of baseline 
cholesterol levels. 
Several trials have demonstrated that high-dose statin started the day before a cardiovascular 
intervention was effective in decreasing the periprocedural myocardial necrosis in subjects 
undergoing percutaneous coronary intervention. In addition to the lipid lowering effect, other 
pleiotropic effects of short-term duration statins are to modify the inflammatory response, 
improve endothelial function, plaque stability and thrombus formation.  With this in mind, we 
believe that high dose statin for at least 3 days prior to orthopedic surgery would be effective at 
decreasing perioperative cardiovascular events.
Beta blockers are widely used in the perioperative period. Multiple randomized trials noted a 
reduction of cardiovascular events in patients undergoing noncardiac surgery. Concerns about 
beta blockers arose following the POISE trial. IN this trial, the reduction in myocardial infarction 
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with the use of beta-blockers was offset by an increased risk of bradycardia, hypotension, 
stroke and death. In this trial, subjects received a high-dose of beta-blocker independent of 
baseline heart rate. Multiple other studies showed a decrease in the incidence of MI, stroke 
and death with perioperative beta blocker use. The discrepancy between trials is likely due to 
the different beta blocking dosing regimens used. The POISE trial initiated beta blocker 
therapy 2-4 hours prior to surgery, prescribing patients up to 400 mg of metoprolol succinate 
on the day of surgery, whereas other trials (such as the DECREASE trial) initiated low-dose 
beta-blockers (bisoprolol 2.5 or 5 mg oncedaily) on average a month prior to surgery.  Given 
the increased catecholamine surge postoperatively, use of a low-dose beta-blocker in 
individuals with an elevated heart rate (similar to the design in the current trial) might further 
reduce the risk of cardiac complications.
 
ACE-inhibitors are effective blood pressure lowering drugs in a variety of settings including 
those with cardiovascular disease and risk factors. Two land-mark trials (HOPE and EUROPA) 
demonstrated that ACE inhibitors could affect the atherosclerotic process and reduce ischemic 
events and complications independent of their effects on heart function and blood pressure. 
Guidelines have incorporated the use of ACE-inhibitors in patients with known cardiovascular 
disease or diabetes and some other risk factors. In an observational study of 481 subjects, 
ACE inhibitors before surgery confer myocardial protection (reducing cardiac troponin release) 
in patients undergoing CABG. Additionally, renin-angiotensin system suppression with an 
ACE-inhibitor may also have a renal protective effect, preserving glomerular filtration rate in 
patients undergoing aortic abdominal aneurysm repair or coronary artery bypass graft surgery.
3. RESEARCH DESIGN AND METHODS
 
3.1.
STUDY OBJECTIVES
The objectives of this study are to determine the efficacy, tolerability and safety of a 3-21 day 
intensive multifactorial intervention comprising behavioral modification and polypharmacologic 
therapy aimed at several modifiable risk factors in high-risk subjects undergoing orthopedic 
surgery will decrease cardiovascular events in the postoperative period (in-hospital or 30-days 
whichever is sooner). We will compare this intervention with a standard of care approach. 
The primary efficacy objective is the composite of cardiovascular events – including death, 
myocardial infarction (MI), stroke, transient ischemic attack (TIA), myocardial necrosis (MN), or 
venous thromboembolism (VTE)
Other markers of Efficacy 
1.
the reduction in the composite of death, MI, stroke, TIA, or MN
2.
the reduction in the composite of death, MI, stroke, or TIA
3.
the reduction in composite of death, MI, stroke, TIA, MN, VTE or reoperation
4.
the reduction in length of stay
5.
the reduction in each individual endpoint
6.
the reduction in reoperation
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Tolerability 
1.
Assessed by reviewing compliance with study medication 
2.
Assessed by reviewing compliance with lifestyle intervention
Safety
1.
The number of adverse events reported and their severity
2.
Reoperation
3.
Major bleeding
4.
Any transfusion within 48 hours of the surgery
i. PRBC
ii. Platelets
iii. Cryo 
iv. FFP
5.
Clinically relevant minor bleeding
6.
Wound complication
7.
Wound drainage
The secondary objective is to demonstrate that a short-term intensive multifactorial intervention 
comprising behavioral modification (smoking cessation, physical activity, and nutrition 
counseling) and polypharmacologic therapy (high-dose statins, ACE-inhibitors, beta blockers, 
and aspirin) aimed at several modifiable risk factors in high-risk subjects undergoing 
orthopedic surgery will improve the subjects risk factor profile (smoking, blood pressure, lipid 
profile, platelet activity, and sedentary lifestyle) measured immediately prior to surgery. 
1. The percent change from baseline in LDL-C, HDL-C, TC, and TG 
2. The percent change from baseline in active smokers 
3. The percent change from baseline in SBP and DBP
4. The percent change from baseline in hs-CRP, 
5. The percent change from baseline in platelet activity
6. The percent change from baseline in nutrition survey
7. The percent change from baseline in exercise survey
Characteristics of Research Population
Number of Subjects
We plan to enroll 550 subjects with approximately 500 completing the study – 250 
subjects in each group.  This number will allow for an estimated 40% reduction in risk.  We 
anticipate a drop out rate of 10% as predicted by OR cancellation rates.  Subjects will be 
identified for study inclusion by the Pre-Admission (PAT) schedule.  Members of the critical 
care staff who are also co-investigators in this study routinely review the PAT schedule.
Gender, Age, Racial and Ethnic Origin of Subjects
We will recruit both males and females and recruitment will be open to all racial and 
ethnic origins.  We will recruit subjects aged 21 and older.
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Vulnerable Subjects
We will be recruiting subjects over the age of 65, but will not recruit any subject with a 
documented or self reported history of cognitive dysfunction.
3.2.
INCLUSION CRITERIA

≥ 21 years of age 

Subjects undergoing open orthopedic surgery of the hip, knee or spine

Surgery is scheduled at least 3 days after PAT visit and no more than 21 days. 

High risk subject cohort
o
Coronary artery disease, or
o
Cerebrovascular disease (prior stroke, TIA or carotid artery disease (>70% 
stenosis), or
o
Peripheral artery disease, or
o
Prior Venous thromboembolism or arterial thromboembolism, or
o
Age ≥ 60 years and 2 of the following

Renal insufficiency (creatinine clearance < 60ml/min)

Diabetes 

COPD

Hypertension 

Active smoker or stopped less than 30 days prior to consent

Cancer (excluding BCC)

Heart Failure
3.3.
EXCLUSION CRITERIA

Known intolerance to statins

Subject is already on maximum dose statin (atorvastatin/Lipitor 80mg daily or 
rosuvastatin/crestor 40mg daily)

Bilateral renal artery stenosis

End stage renal disease (receiving dialysis or CrCl <30ml/min)

Known allergy or intolerance to ACE-inhibitor (other than cough) or Angiotensin receptor 
blocker (e.g. angioedema, hyperkalemia)

Known allergy or intolerance to beta blockers 

Known sick sinus syndrome not treated with permanent pacemaker

Known greater than first degree AV block not treated with a pacemaker 

Excessive alcohol intake 

Acute Coronary Syndrome requiring hospitalization within 1 month

Stroke within 1 month 

Known pregnancy 

Severe co-morbid condition with life expectancy < 6 months

Inability to give informed consent or adhere to follow-up as per protocol 

Current participation in another investigational drug or device trial 
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3.4.
SCREENING AND RECRUITMENT
An informational flier will be given to each patient during their pre surgical visit at their 
orthopedic surgeon’s office.  If the patient has co-morbidities that determine enrollment in the 
study, their surgeon will briefly introduce the study to the patient.  He or She will tell the patient 
that more information will be given to them in PreSurgical (PreAdmission) testing.  If the patient 
agrees to learn more about the study, a member of the study team will call the patient prior to 
their PAT visit using the script, attached.  If a patient does not want to be spoken to in PAT, or 
changes their mind at any time, they can let the surgeon’s office staff, study staff or PAT staff 
know and the staff will communicate this to a member of the study team via email,  phone, text 
or personal communication. Any patient not refusing communication regarding research may 
be approached in vis phone prior to PAT and/or prior to any PAT procedures being performed, 
if a pre phone call was unsuccessful.
Subjects will be pre-screened by the surgeon at the time of their clinically indicated 
appointment for potential inclusion/exclusion. The research team will obtain a list of scheduled 
appointments for the day and assess the list for patients who have potential eligibility for the 
study. All potentials subjects will be pre-screened again daily by the study staff. Based on 
preliminary data, approximately 20% of the pre-screened patients are expected to be eligible 
for the study. A member of the research staff will call the subjects prior to their appointment. All 
study related discussion will occur in a private setting.  The study personnel will discuss the 
study in its entirety during the patients PAT visit in accordance with HIPAA and PPHS 
standards.
3.5.
TIME FRAME
Enrollment will begin in the beginning of 2013, once Institutional Review Board approval is 
obtained. The study will take approximately up to 24 months to enroll 550 subjects. 
3.6.
INFORMED CONSENT
Only current, Institutional Review Board (IRB) stamped consent forms will be used to obtain 
informed consent. The subject’s signed and dated informed consent form will be obtained 
before conducting any procedure specific to the study.  A copy of the completed written 
informed consent form will be provided to the subject and placed in their patients records and 
the original ICF will be maintained in the study binder.  A note will be placed in the subjects’ 
medical chart indicate their participation in this research protocol.
Consent will be presented to each subject in a private setting.  The study staff will limit 
distractions and interruption to the best of their ability.  Prior to signing the informed consent 
form, subjects will be given full oral and written information about the nature, purpose, potential 
risks and benefits of the study. Subjects will be notified of the voluntary nature of the study and 
that subjects may discontinue at any time without affecting their health care. Subjects will be 
given the opportunities to ask questions and allowed sufficient time to consider the study 
information.
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Cost to subjects:
All study related costs will be provided by Departmental funds.  Participants will not 
incur any study related costs.  The cost of routine care will be charged to the patient and/or the 
patients insurance.
3.7.
RANDOMIZATION
A blocked randomization scheme with random block size will be performed. The study 
statistician will arrange the randomization code before the study begins based on the expected 
number of participants estimated using power and sample size analysis. The randomization 
will be performed using routines for random number generation available in SAS. Envelops 
with study arm assignments will be given to the project manager. Randomization concealment 
will be ensured, as the randomization code will not be released until the patients are recruited 
in the trial (informed consent is signed) and all baseline measures are taken. Specifically, upon 
certifying an eligibility checklist for a potential participant deemed eligible, the study physician 
will notify the research assistant who will open the next envelope. Study staff who perform 
assessments will be blinded to participants’ intervention assignment. 
Subjects will be approached for enrollment by the research coordinator or a member of the 
clinical research team. If informed consent is obtained, subjects will be randomized (see figure 
above) in a 1:1 manner to either:
•
Usual Care (in accordance with national guidelines)
•
Personalized optimization (multifactorial intervention comprising behavioral modification 
and polypharmacologic therapy aimed at several modifiable risk factors)
3.8.
METHODS
Study Overview
Following randomization, study participants will be assigned into one of two groups: usual care 
or personalized optimization. 
Subjects in the usual care group will receive standard of care counseling and treatment in 
accordance with national guidelines.  This will include medical clearance, if appropriate, for 
surgery.
Subjects in the personalized optimization group will receive an intensive multifactorial 
intervention comprising behavioral modification (smoking cessation, physical activity, and 
nutrition counseling) and polypharmacologic therapy (high-dose statins, ACE-inhibitors, beta 
blockers, and aspirin) aimed at several modifiable risk factors. 
A. Statins – 
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Initiate/titrate statin to maximum dose. All subjects whether they are on a statin at 
baseline or not, should be placed on maximum dose statin (atorvastatin 80mg daily). (if 
a subject is on a statin other than the ones being used, we will switch therapies to the 
ones being used in the trial till the day of surgery). Medicine will be taken daily, including 
the day of the operation. Following surgery, all subjects will receive their usual care.  
See appendix #2 for how we will deal with different circumstances.
B. Beta blockers
If the subject’s heart rate is elevated (HR >75bpm) – will treat with a low-dose beta 
blocker (metoprolol 25mg). Medicine will be taken daily, including the day of the 
operation. The appendix #2 details different circumstances for beta blocker use. If the 
subject is on a beta-blocker at baseline that is not maximally dosed and the HR remains 
>75bpm, we will give metoprolol 25mg to be taken twice daily. Following surgery, all 
subjects will be treated as usual care.  
C. ACE-inhibitors / Angiotensin Receptor Blocker (ARB)
If blood pressure is elevated SBP > 130 mmHg or if DBP >90 mmHg – will treat with a 
low-dose ACE-inhibitor (lisinopril 5mg). Medicine will be taken daily, including the day of 
the operation. The appendix #2 details different circumstances for ACE-inhibitor/ARB 
use. If the subject is on an ACE-inhibitor or ARB at baseline that is not maximally dosed 
and the SBP > 130 mmHg or if DBP >90 mmHg, we will give lisinopril 5mg daily).  
Following surgery, all subjects will be treated as usual care.  
D. Smoking cessation
If the subject is a smoker, will counsel the subject on quitting, start a behavioral 
intervention program, and will offer nicotine replacement therapy till the day of surgery. 
Subjects will be given the number for the quit hotline. The goal will be to reduce the 
number of cigarettes smoked during the period of time before surgery if they cannot (or 
do not) intend to quit altogether. 
E. Physical activity 
Will discuss the importance of increasing physical activity prior to surgery. Many 
subjects will be unable to exercise using traditional methods (thus requiring orthopedic 
surgery). We will encourage different forms of physical activity depending on what is 
tolerated (e.g. hand grip exercise, arm rowing, or walking).
A target heart rate will not be used for monitoring. We will encourage some exercise – 
based on simple stretches, yoga, walking, bicycling, swimming – for up to 30 minutes a 
day. A hand out with simple exercises will be handed out. Physical activity will be 
monitored based on the subject’s survey response to how much activity they have done.
F. Nutrition counseling 
Will discuss the importance of improving nutrition prior to surgery. Will encourage an 
ideal healthy heart diet which includes: consumption of fruits and vegetables (>4.5 
cups/day), fish (>two 3.5-oz servings/week), fiber rich whole grains (> three 1-oz-
equivalent servings/day), limit sodium intake (AHA goal is <1500 mg/d), and limit sugar 
sweetened beverages (AHA goal is <36-oz/week). We will also counsel the subject to 
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refrain from fried foods and fast foods during the period prior to surgery.  (see Appendix 
1)
 
3.9.
TABLE 1: STUDY SCHEDULE 
ECG 
and blood work are routine clinical care
^ +/- 1 day;  *whichever is sooner
SOC, standard of care
13
Treatment Period 
Baseline 
Pre- Surgical 
Testing
Pre-
operative
POD2^
Discharge or 
30 calendar 
days*
Informed Consent
X
Demographics
X
 Medical History
X
Physical exam and vitals
X
X
Lipid profile
X
X
Platelet Activity Profile
X
X
X
Basic Metabolic Panel 
X (SOC)
Inflammatory Markers
X
X
X
Smoking assessment
X
X
Lifestyle Assessment
X
X
ECG
X (SOC)
X
Troponin
X
Adverse Event Assessment
X
X
X
Review of concomitant 
medications
X
X
X
X
Study drug dispensing
X
Review medication 
compliance 
X
X
Cardiovascular endpoint 
assessment
X
X
Biospecimen collection
X
X
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Baseline Visit/Pre-Admission testing: 
A. Inclusion/exclusion criteria
B. Informed consent
C. Randomization
D. Blood collection
a. Lipid panel
b. Inflammatory markers
c. Platelet activity
E. ECG
F. Collection of data from medical chart
a. Demographics
b. Medical history
c. Surgical history
d. Medication history
e. Smoking history
f.
Physical exam
g. Lifestyle survey
G. Treatment group: dispense treatment medications, instruction for smoking cessation, 
instruction for exercise and nutrition
Pre-operative: 
A. Patient in the treatment group may receive phone calls by a member of the research 
staff to encourage protocol compliance and answer any questions.
B. Adverse event assessment
Day of Surgery:
A. Blood collection
a. Lipid profile
b. Inflammatory markers
c. Platelet activity
B. Treatment group interview regarding protocol compliance
C. Lifestyle survey
D. Collection of data from medical chart
a. Laboratory results 
PACU:
A. Blood collection
a. Troponin (usual care, if clinically indicated)
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B. Collection of data from medical chart
a. Surgical record
i. Planned surgery
ii. Actual surgery
iii. Incision time
iv. Surgery end time
v. Surgical events
b. Anesthesia record
i. Anesthesia start time
ii. Anesthesia end time
iii. Anesthesia medication administration
iv. Anesthesia type
v. Anesthesia events
c. Laboratory results
d. Physical exam 
e. Vital signs
POD 2 +/- 1 day: 
A. ECG
B. Blood collection
a. Troponin
b. Platelet activity and inflammatory biomarkers
C. Collection of data from medical chart
a. Adverse events
b. Review of concomitant medication 
c. Review of cardiovascular end-points
d. Laboratory results
e. Physical exam 
f.
Vital signs
POD 3, Discharge or 30 days (whichever is sooner):
A. Collection of data from medical chart
a. Adverse events
b. Review of concomitant medication 
c. Review of cardiovascular end-points
d. Laboratory results
e. Physical exam 
f.
Vital signs
Long-term follow-up (phone calls every 6 months for 3 years)
During the prior 6-months did the subject experience any of the following events:
Death
 yes   no
Reoperation
 yes   no
MI
 yes   no
Coronary Stent  
 yes   no
CABG
 yes   no
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Stroke/TIA
 yes   no
DVT
 yes   no
PE
 yes   no
3.10. TREATMENT COMPLIANCE
Patients will be expected to comply with all study related procedures.  Compliance will be 
measured by pill counting and by the validated Moriskey survey which assesses compliance. 
Patients may be withdrawn from the study for any of the following reasons:
a. Cancelation of surgery
b. At patient’s request
3.11. PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Atorvastatin will be supplied in 80mg tablets. Subjects randomized to the multiple intervention 
arm will be given 80mg of atorvastatin to take daily from randomization till the day of surgery. 
Based on the inclusion criteria, subjects will take this regimen for anywhere between 3-21 days. 
We estimate the average to be approximately 7-days. Atorvastatin will be provided free of 
charge to the participant. Atorvastatin is an approved drug for subjects with cardiovascular 
disease or those without CHD, but with multiple risk factors. 
Lisinopril will be supplied in 5mg tablets. Any subject randomized to the multiple intervention 
arm with a SBP above 130mmHg or DBP above 90mmHg will receive lisinopril 5mg to be 
taken daily till the day of surgery.  A dose of 5mg was chosen because its effect on systolic 
blood pressure is minimal and we know that lisinopril has a cardioprotective effect. If the 
subject has a K>5mEq/L, the subject will not receive an ACE-inhibitor or ARB.
Metoprolol will be supplied in 25mg tablets. Any subject randomized to the multiple intervention 
arm with a HR above 75 bpm will receive metoprolol 25mg to be taken twice daily till the day of 
surgery.  
Lisinopril, atorvastatin and metoprolol will be provided free of charge to the participants in the 
treatment arm. All medicines will be provided in a pill box with clear instructions on their use. 
Subjects will be asked to bring back their pill box for pill counting on day of surgery.
All study medications will be stored in locked cabinets accessible only to study staff.  Once the 
patient has been consented and randomized to the treatment arm, a licensed practitioner will 
dispense the necessary medications into a 'days of the week' pill box labeled with the patients 
name.  Individualized, specific instructions for self-administration will be included with the pill 
box along with a 24 hour contact number for questions or concerns.  A licensed practitioner will 
then personally present the pill box, instructions and contact numbers to each treatment 
participant. If there are extra pills, we will destroy any returned medication as per hospital 
protocol.  
3.12. CONCOMITANT MEDICATIONS
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All concomitant medications will be maintained at the same dosage during the course of the 
study unless the changes to the medications or the dose are clinically mandated. 

If a subject randomized to the multiple intervention arm is taking a different statin, they 
will stop that drug and be given atorvatstain 80mg. See appendix #2 for examples.

If a subject randomized to the multiple intervention arm is taking a different ACE-
inhibitor that is not maximally dosed and their systolic blood pressure is greater than 
130mmHg, we will provide 5mg lisinopril daily. See appendix #2 for examples.

If a subject randomized to the multiple intervention arm is taking a different beta-blocker 
that is not maximally dosed and their heart rate is greater than 75 bpm, we will provide 
metoprolol 25mg daily. See appendix #2 for examples.
3.13. BLOOD TESTS
Following enrollment, subjects will have their blood drawn and another blood draw immediately 
before surgery. Blood collection will be done using standard aseptic phlebotomy techniques. 
 In short, after cleansing of the venipuncture site with an alcohol wipe and removal of excess 
alcohol with sterile gauze, a tourniquet will applied to the patient’s bicep region.  A 19g or 21g 
butterfly needle will be inserted into the antecubital vein and free-flowing blood will be collected 
with minimal trauma and stasis.  The needle will be removed when blood collection is complete 
and sufficient pressure will be applied using sterile gauze at the puncture site until cessation of 
bleeding.  A sterile band-aid will be applied to cover the venipuncture site.  For each patient, 
no more than 30 cc (≈ 2 tablespoons) of blood will be collected in red (no anticoagulant) top, 
lavender (EDTA anticoagulant) top, green (heparin) and blue (sodium citrate anticoagulant) top 
tubes. Approximately 15 cc of blood will be used for the different measurements of platelet 
function and inflammation, and approximately 15 cc of blood will be used to for plasma and 
sera separation (for cardiovascular biomarkers). The samples will be stored in HJD 15th floor 
Musculoskeletal lab before being transferred to Dr. Berger’s lab in Smilow 8th floor for analysis 
without any identifying information other than a code number. The code number will not be 
based on any information that could be used to identify the subject (for example, social 
security number, initials, birth date, etc). The master list linking names to code numbers will be 
kept in a locked file cabinet, separate from all research information.  
The specimen will be analyzed upon completion of the study for cardiovascular biomarkers as 
described above. We can only measure this at the end of the study because we will need to 
analyze this in bulk for quality control. These serum and plasma samples will not be used or 
stored for any research other than what is describe in this protocol.
3.14. DATA ANALYSIS and POWER ANALYSIS
The primary objective of these analyses is to compare the effects of a personalized 
optimization approach on a composite of cardiovascular events. The secondary objective is to 
compare the effects of a personalized optimization approach on a panel of cardiovascular 
biomarkers, including lipid values, metabolic and inflammatory risk and platelet activity, as well 
as healthy lifestyle. This study will allow us to determine if measures of cardiovascular 
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biomarkers or lifestyle change are mediators of cardiovascular risk reduction observed in 
response to randomization. 
Data Management. All subjects will be assigned a unique identification number at random 
upon study entry. All subsequent data will be stored on a secure electronic database. 
Identifying information will be kept in a locked secure location by a member of the research 
study. All entries will be double-checked against source documents for accuracy.
Descriptive analyses Descriptive statistics (means, medians, frequencies) will be used to 
characterize demographic, dietary, clinical, and laboratory variables of the study participants in 
each study group. Distribution of the primary outcome variables and other demographic, 
dietary, and clinical variables will be examined among study participants.
Overview of Univariate Analyses for Aims 1,2, and 3 All comparison between the treatment 
and control group will be based on intention-to-treat analysis. The intention-to-treat population 
is defined as all subjects randomized in the trial, and classified based on randomized treatment 
assignment. All statistical tests will be 2-sided. Appropriate multiple testing procedures will be 
applied. Continuous variables will be compared using t-test and/or Wilcoxon sum rank test as 
appropriate. Categorical variables will be compared using chi-square test and/or Fisher’s exact 
test. Many lipid parameters are continuous variables, and many of them are apparently not 
normally distributed, and therefore nor-parametric statistical methods are appropriate in many 
analyses. 
In addition to analyses outlined in the overview, the following analyses specific to each aim are 
planned. 
Aim 1: Effect of intervention on frequency of cardiovascular events in postoperative period 
Logistic regression models will be fit to quantify an effect of intervention on occurrence of a 
specific cardiovascular event or on a binary indicator of at least one of the cardiovascular 
events . Multinomial regression model will be used to quantify an effect of intervention on a 
number of cardiovascular events. Odds Ratios and Relative Risk will be inferred accompanied 
by 95% Confidence Intervals.  Assumptions will be checked and transformations, such as log- 
and Box-Cox, will be considered. 
Aim 2: Effect of intervention on risk profile prior surgery Analysis of variance (ANOVA) will be 
used to examine an effect of intervention on risk profile factors prior to surgery. Multivariate 
Analyses of Variance (MANOVA) will be employed to examine an effect of intervention on a 
multivariate vector of risk factors. 
Aim 3: Relationship between modifiable risk factors and cardiovascular events Logistic and 
multinomial regression models will be used to examine the relationship between 
cardiovascular events and modifiable risk factors. Main effects of modifiable risk factors will be 
examined based on univariate regression models. Additive and synergistic effects will be 
examined based on multivariate regression models. Treatment – by- modifiable risk factors 
interactions will be estimated to examine whether the intervention can mediate the effect of 
modifiable risk factors. Odds Ratios and Relative Risk will be inferred accompanied by 95% 
Confidence Intervals.  Multivariate models will be constructed based on a combination of our a 
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priori biomedical knowledge and statistical model choice techniques. Dimensionality reduction 
techniques will be considered to aggregate effects of multiple risk factors, e.g. to infer a 
principal combination of platelet activity measures. 
Analysis of Missing Data Missing data will be investigated by inferring a relationship between 
baseline characteristics/risk factors and a 0-1 indicator that defines whether or not a 
measurement is observed. This analysis will help to identify factors that are likely to cause 
measurements to be missing. These analyses will employ regression techniques (e.g., multiple 
linear, non-linear, and log-linear), possibly with model averaging and model selection. The goal 
for addressing missing data carefully is not because we intend to impute missing values, but 
rather to better understand its causes. 
Sample Size and Power Analysis. Power is estimated for the primary endpoint of a composite 
of cardiovascular events in the table below assuming a sample size of 550 per treatment group 
with 10% loss to follow-up, estimated proportion of events based on prior data from this group, 
the presence of a clinically meaningful 40% difference in events between groups. These 
calculations demonstrate that with a sample of 500 subjects (250 per treatment group) the two-
sided z-test of proportion has 80% power to detect clinically important differences in a 
composite of cardiovascular events at the 0.05 significance level. 
3.15. INTERIM ANALYSIS FOR SAFETY AND EFFICACY
Interim analysis will be performed when 50% of participants are enrolled. 
The trial will be stopped for efficacy based on the following power analyses. With 125 
participants per treatment arm, two-sided Fisher’s exact test of proportions will have 80% 
power to detect the following differences in event rates between the two study arms.
Expected event rate in the usual care 
arm
25%
30%
35%
Significance 
level
11%
15%
19%
0.05
12%
16%
20%
0.10
Estimated event rate in the intervention 
arm
14%
18%
22%
0.20
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The trial will be stopped for safety based on the following power analyses. With 125 
participants per treatment arm, two-sided Fisher’s exact test of proportions will have 80% 
power to detect the following differences in event rates between the two study arms.
Expected event rate in the usual care 
arm
25%
30%
35%
Significance 
level
42%
48%
53%
0.05
40%
46%
51%
0.10
Estimated event rate in the intervention 
arm
38%
44%
49%
0.20
Overall power and analysis lan was performed using the following program: 
Hintze, J. (2008) PASS 2008 NCSS LCC Kaysville, Utah
5.
SAFETY MONITORING PLAN
 
Our assessment of moderate risk does not preclude the potential for anticipated and/or 
unanticipated adverse events, serious or otherwise. It is not possible to predict with certainty 
the absolute risk in any given individual or in advance of first-hand experience with the 
proposed study methods. Therefore, we provide a plan for monitoring the data and safety of 
the proposed study as follows: 
5.1. 
ATTRIBUTION OF ADVERSE EVENTS
Adverse events will be monitored for every subject participating in the study and attributed to 
the study procedures/design by the Principal Investigator (Jeffrey S Berger) according to the 
following categories: 
a. Definite: Adverse event(s) will clearly be related to the intervention. 
b. Probable: Adverse event(s) will likely be related to the intervention. 
c. Possible: Adverse event(s) may be related to the intervention. 
d. Unlikely: Adverse event(s) will doubtfully be related to the intervention. 
e. Unrelated: Adverse event(s) will clearly not be related to the intervention.
5.2.
PLAN FOR GRADING ADVERSE EVENTS 
The following scale will be used in defining/grading the severity of adverse events noted during 
the study: 

0 No adverse event 

1 Mild adverse event 

2 Moderate adverse event 

3 Severe adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization, 
a 
persistent 
or 
significant 
disability/incapacity 
or 
congenital 
anomaly/birth defect 

4 Life-threatening or disabling adverse event 
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
5 Fatal adverse event 
5.3. 
PLAN FOR REPORTING SERIOUS UNANTICIPATED ADVERSE EVENTS 
a. Serious unanticipated adverse events will be reported within 48 hours to the IRB 
b. Serious anticipated adverse events will be reported within 48 hours to IRB whenever 
their magnitude or frequency exceeds expectations 
c. Adverse events will be deemed serious in nature if graded as 3 or higher according to 
the scale in item #2 above. 
5.4. 
PLANS FOR REVISING AND REPORTING NON-SERIOUS ANTICIPATED AND 
UNANTICIPATED ADVERSE EVENTS 
The principal investigator, Jeffrey S Berger will continually be monitoring the frequency and 
severity of the adverse events in conjunction with the NYUMC IRB to determine if 
modifications to the protocol or consent form are required. 
6.
REPORTING OF SERIOUS ADVERSE EVENTS
A summary of unanticipated and anticipated (UNATP and ATP respectively) adverse events 
will be reported to IRB at a minimum of every 12 months (including when re-approval for the 
protocol is sought). The summary will include the number of subjects enrolled and a summary 
of graded adverse events to date per the following table:
Attribution
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
UNATP/ATP 
UNATP/ATP 
UNATP/ATP 
UNATP/ATP 
UNATP/ATP 
Unlikely 
Possible 
Probable 
Definite 
Totals 
Total 
subjects 
enrolled to 
date 
 
6.1. 
PERSONNEL RESPONSIBLE FOR THE SAFETY REVIEW AND ITS FREQUENCY
An independent Data and Safety Monitoring Board (DSMB) will be established. The DSMB will 
be responsible for monitoring the data and conducting performance of safety reviews at a 
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minimum of every 6 months. Reports for anticipated/unanticipated serious adverse events and 
the form outlined above under item #4 for routine adverse events. During the review process, 
the DSMB will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment and will relay this information to the PI.
The DSMB will be composed of 3 individuals who have expertise in the field, experience in the 
conduct of clinical trials, and statistical knowledge. 
7.
POTENTIAL RISKS/PROTECTION AGAINST RISK
The risks associated with this study are deemed to be moderate for the following reasons: 
1) The risks associated with phlebotomy are more than minimal. 
2) The risk associated with statins are more than minimal. Statins in the doses used in this 
research plan have been well tolerated in previous clinical use and clinical research 
studies of normal subjects, subjects at risk for cardiovascular disease and patients with 
cardiovascular disease without major adverse effects. 
3) The risks associated with beta blockers are considered more than minimal, although in 
our experience and in the literature low-dose (dose used in the research plan) beta 
blockers and ACE-inhibitors have been very well tolerated in both subjects at risk for 
cardiovascular disease and patients with established cardiovascular disease.  
4) The risks associated with other multifactorial approach are minimal. 
5) Proper subject selection according to inclusion/exclusion criteria as described in the 
protocol minimizes the risks to study subjects. 
7.1. 
ALLERGIC REACTIONS
Patients with a hypersensitivity reaction to the study medication will discontinue the study 
medications and treated in the standard manner using histamine receptor blockers and or 
corticosteroids in accordance with the severity of the hypersensitivity of the reaction. To 
minimize this risk, we are excluding subjects with a known intolerance to statins.
7.2.
HYPOTENSION/BRADYCARDIA
Patients receiving an ACE-inhibitor and/or beta blocker may be at risk for hypotension or 
bradycardia, and a reduction in the dose of the concomitant agent may be necessary. This 
study will only provide ACE-inhibitors and beta-blockers to subjects with an elevated blood 
pressure and heart rate, respectively (thus, the risk for hypotension/bradycardia is low). 
7.3.     MUSCLE DAMAGE
Atorvastatin which can rarely lead to a very serious, possibly fatal condition called 
rhabdomyolysis.  Rhabdomyolysis is the breakdown of muscle fibers that leads to the release 
of muscle fiber contents into the bloodstream which is harmful to the kidney and may cause 
kidney damage.  Patients develop muscle pain, weakness and/or tenderness must seek 
medical attention immediately.  Since this study uses statin therapy for a very short period of 
time, these risks are very rare.
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For beta blockers, we will only be giving low-dose beta blocklers to subjects with a heart rate > 
75bpm – thus, the side effects from the heart rate lowering should be minimal. Nonetheless – 
we will tell the subject that if they feel light headed, pre-syncopal or any syncope – they should 
stop the therapy.
For ace-inhibitors, we will only be giving low-dose ace-inhibitors to subjects with an elevated 
blood pressure – thus, the side effects from the blood pressure lowering should be minimal. 
Nonetheless – we will tell the subject that if they feel light headed, pre-syncopal or any 
syncope or if they develop angioedema – they should stop the therapy.
For statins, everyone randomized to the intervention arm will be getting high dose atorvastatin 
– since the subject will be receiving the drug for a short period of time (3 – 21 days) – we do 
not expect any serious side effects. We will counsel the subject that if they develop severe 
cramping symptoms – they should stop their therapy and let the research coordinator know. 
Otherwise, since the side effects are trivial for such a short period of time – there will be no 
tests or monitoring.
7.4.      BLOOD COLLECTION
The participant will be asked to give a small sample of blood at each collection. The discomfort 
associated with giving blood include pain, bruising, and rarely, fainting or infection.
8. POTENTIAL BENEFIT TO THE SUBJECTS
The study participant may benefit from closer than usual follow-up care. The participant may 
not be helped by taking part in this study, but their participation may lead to knowledge that will 
help others.
9.
DATA MANAGEMENT
Patient data will be recorded directly on to CRF with unique patient number assigned at study 
entry. The study coordinator will transfer information from the CRF to an electronic access 
database created specifically for this study using only the unique patient number. Laboratory 
results will be transposed directly to the database. All entered data will be double checked.
10. 
ETHICAL ASPECTS OF THE PROPOSED RESEARCH
10.1. ETHICAL CONDUCT OF THE STUDY
The study will be performed in accordance with the Declaration of Helsinki, Good Clinical 
Practice, and applicable regulatory requirements. In this study we are using an FDA approved 
drug outside its current indication and subjects will be informed of this before obtaining 
informed consent.  Similar studies have been conducted in the past (as described in Relevant 
Studies Section) without excess of adverse events reported. 
                            
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10.2. CONFIDENTIALITY
Personal and medical information about the study participant will be kept confidential. This 
information will include any information about the study participant that the study doctor needs 
to do the study, including information from the tests. The study participant records also will 
include other identifying information about them, such as their name and address.
The study participant information will be kept in secured file. The study participants have the 
right to see and copy their information. At any time, the study participant may ask to see their 
personal information (such as name and address) and correct it if necessary. However, if the 
study participants sign this form, they might not be able to see or copy some of their 
information until after all participants finish the study.
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11. 
Literature Cited:
Benedetto U, Melina G, Capuano F, Comito C, Bianchini R, Simon C, Refice S, Angeloni E, 
Sinatra R. Preoperative angiotensin-converting enzyme inhibitors protect myocardium from 
ischemia during coronary artery bypass graft surgery. J Cardiovasc Med 2008; 9: 1098–1103.  
Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, Mussardo M, Montorfano M, 
Ricciardelli B, Colombo A. Novel approaches for preventing or limiting events (Naples) II trial: 
impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J 
Am Coll Cardiol. 2009 Dec 1;54(23):2157-63.
Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, 
Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka 
M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-
cardiac surgery (POISE trial): a randomised controlled trial. Lancet 2008; 371: 1839–1847.  
Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of 
atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary 
intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial 
Damage During Angioplasty) Randomized Trial. J Am Coll Cardiol. 2009 Aug 4;54(6):558-65. 
Ferguson Jr TB, Coombs LP, Peterson ED. Preoperative beta-blocker use and mortality and 
morbidity following CABG surgery in North America. JAMA 2002; 287: 2221–2227.  
Fleisher LA, Poldermans D. Perioperative beta blockade: where do we go from here? Lancet 
2008; 371: 1813–1814.  
Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with 
stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial 
(the EUROPA study). Lancet 2003; 362: 782–788. 
Leeuw PW, Birkenhager WH. Short- and long-term effects opf ramipril in hypertension,. Am J 
Cardiol 1987;59:79D-82D
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart 
Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145–153.  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020702Orig1s060lbl.pdf    
(Labeling for atorvastatin)
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12. 
Appendices
Appendix #1
Tips for Reducing Sodium in the Diet
• Read the Nutrition Facts label to compare and find foods lower in sodium. You’ll be 
surprised to find that even foods in the same category have different amounts of 
sodium!
• Choose fresh fruits and vegetables, when possible.
• Limit the amount of processed foods you eat and your portion size.
• Avoid adding salt when cooking and/or eating.
• Learn to use spices and herbs to enhance the taste of your food. Most spices naturally contain very 
small amounts of sodium, but read the label to be sure.
• Add fresh lemon juice instead of salt to fish and vegetables.
• Specify how you want your food prepared when dining out. Ask for your dish to be prepared without 
salt.
• Take control of what’s in your food by cooking more at home.
• Choose foods with potassium. They counter the effects of sodium and may help lower your blood 
pressure.
 
Tips for Reducing Sugar in Your Diet:
Take sugar (white and brown), syrup, honey and molasses off the table — out of sight, out of 
mind!
• Cut back on the amount of sugar added to things you eat or drink regularly like cereal, 
pancakes, coffee or tea. Try cutting the usual amount of sugar you add by half and 
wean down from there, or consider using an artificial sweetener.
• Buy sugar-free or low-calorie beverages. 
• Buy fresh fruits or fruits canned in water or natural juice. Avoid fruit canned in syrup, 
especially heavy syrup.
• Instead of adding sugar to cereal or oatmeal, add fresh fruit (try bananas, cherries or 
strawberries) or dried fruit (raisins, cranberries or apricots).
• When baking cookies, brownies or cakes, cut the sugar called for in your recipe by one-third 
to one-half. Often you won’t notice the difference.
• Instead of adding sugar in recipes, use extracts such as almond, vanilla, orange or lemon.
• Enhance foods with spices instead of sugar; try ginger, allspice, cinnamon or nutmeg.
• Substitute unsweetened applesauce for sugar in recipes (use equal amounts).
• Try non-nutritive sweeteners such as aspartame, sucralose or saccharin in moderation. Non-
nutritive sweeteners may be a way to satisfy your sweet tooth without adding more 
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calories to your diet. The FDA has determined that non-nutritive sweeteners are safe.
Fruits and Vegetables
An average adult consuming 2,000 calories daily should aim for 4.5 cups of fruits and 
vegetables a day. Also, variety matters, so try a wide range of fruits and veggies
 
Go fish
The American Heart Association recommends eating fish (particularly fatty fish) at least 
two times (two servings) a week. Each serving is 3.5 ounce cooked, or about ¾ cup of 
flaked fish. Fatty fish like salmon, mackerel, herring, lake trout, sardines and albacore tuna are 
high in omega-3 fatty acids. 
Tips for eating fish:
• Enjoy fish baked or grilled, not fried. 
• Choose low-sodium, low-fat seasonings such as spices, herbs, lemon juice and other 
flavorings in cooking and at the table.
 
Fiber
Try to get about 25 grams of fiber each day.
Whole-grain choices
• whole-grain bread (such as 100% whole-wheat bread)  
• whole-grain cereal (about 1 cup wheat flakes)
• whole-grain cereal, brown rice, or whole-wheat pasta
whole-grain crackers
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Appendix #2:
Statins Therapy:
In the personal optimization arm, all subjects will receive 80mg atorvastatin starting at PAT. 

If the subject is on no statin – they will be counseled to take atorvavstatin 80mg daily 
through the day of surgery. 

If the subject is on another statin, we will provide oral and written instructions to hold 
their baseline statin and take the atorvastatin 80mg daily till the day of surgery. 
Following surgery, subjects will go back on their baseline regimen and will be treated as per 
usual postoperative care.
Beta-blockers:
In the personal optimization arm, all subjects with a heart rate above 75 beats per minute (bpm) 
will receive 25mg metoprolol twice daily starting at PAT. 

If the subject is not on a beta blocker – they will be counseled to take metoprolol 25mg 
twice daily till the day of surgery. 

If the subject is on a beta blocker that is not maximally dosed (see table below), we will 
provide metoprolol 25mg twice daily to be given throughthe day of surgery. 

If the subject is on a beta blocker that is maximally dosed, they will not be given an 
additional beta blocker
Following surgery, both groups will be treated as per usual postoperative care.
Beta Blocker
Maximum Dose
Atenolol (tenormin)
100mg daily
Betaxolol (Kerlone)
20 mg daily
Bisoprolol (Zebeta)
20 mg daily
Carvedilol (Coreg , Coreg CR)
50 mg daily
Labetalol (Normodyne)  
2400 mg daily
Metoprolol tartrate (Lopressor)  
400 mg daily (300mg in the elderly >65 years of age)
Metoprolol-succinate (Toprol-XL)
200mg daily
Nadolol (Corgard)
320mg daily
Pindolol (Visken)  
60mg daily
Propranolol (Inderal)
640 mg/day
Sotalol (Betapace)  
320 mg daily
Timolol (Blocadren)  
60 mg daily
ACE-Inhibitors/Angiotensin Receptor Blocker (ARB):^
In the personal optimization arm, all subjects with a systolic blood pressure (SBP) >130mmHg 
or diastolic blood pressure (DBP) >90mmHg will receive 5mg lisinopril daily starting at PAT. 

If the subject is not on an ACE-inhibitor or ARB – they will be counseled to take lisinopril  
5mg daily through the day of surgery.* 

If the subject is on an ACE-inhibitor or ARB that is not maximally dosed (see table 
below), we will provide lisinopril 5mg daily to be given till the day of surgery.* 

If the subject is on an ACE-inhibitor or ARB that is maximally dosed, they will not be 
given an additional ACE-inhibitor or ARB
Following surgery, both groups will be treated as per usual postoperative care.
^if the subject has a K>5mEq/L, the subject will not receive an ACE-inhibitor or ARB
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*if the subject has known cough intolerance to ACE-inhibitor, they are excluded from the study
Angiotensin Converting Enzyme 
(ACE) Inhibitors
Maximum Dose
Benazepril (Lotensin)
80 mg daily
Captopril (Capoten)
150 mg daily
Enalapril (Vasotec)
40 mg daily
Fosinopril  (Monopril)
80 mg daily
Lisinopril (Prinivil, Zestril)
80 mg daily
Moexipril  (Univasc)
30 mg daily
Perindopril  (Aceon)
16 mg daily
Quinapril (Accupril)
80 mg daily
Ramipril (Altace)
20 mg daily
Trandolapril (Mavik)
8 mg daily
Angiotensin II Receptor Blockers
Maximum Dose
Candesartan (Atacand)
32 mg daily
Eprosartan Mesylate (Teveten)
400 mg daily
Irbesartan (Avapro)
300 mg daily
losartan (Cozaar)
100 mg daily
Olmesartan (Benicar)
40 mg daily
Telmisartan (Micardis)
80 mg daily
Valsartan (Diovan)
320 mg daily
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