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Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th , 2010 LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS Clinical Pharmacy Director & PGY1 Residency Clinical Pharmacy Director & PGY1 Residency Director Director PHS Claremore Indian Hospital PHS Claremore Indian Hospital Clinical Assistant Professor, University of Clinical Assistant Professor, University of Oklahoma College of Pharmacy Oklahoma College of Pharmacy 1

Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 1: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Cardiovascular Risk UpdatesCardiovascular Risk UpdatesUSPHS Scientific and Training Symposium – Pharmacy Category

May 25th, 2010

LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSLCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSClinical Pharmacy Director & PGY1 Residency DirectorClinical Pharmacy Director & PGY1 Residency Director

PHS Claremore Indian HospitalPHS Claremore Indian HospitalClinical Assistant Professor, University of Oklahoma College of Clinical Assistant Professor, University of Oklahoma College of

PharmacyPharmacy

1

Page 2: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Objectives

• Identify novel cardiovascular biomarkers that correlate with enhanced cardiovascular risk

• Review contemporary literature likely to impact future cardiovascular guidelines

• Analyze new therapeutic approaches aimed at reducing cardiovascular morbidity and mortality

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Page 3: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Overview• Lipid/Lipoprotein review

• Review of NCEP ATP III* guideline targets

• Current shortfalls in CV risk assessment

• Recent studies of interest– INTERHEART– Emerging Risk Factors Collaboration– JUPITER

• Predictions??

3

*Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on detection , evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

Page 4: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 5: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Lipid Component Review

• Lipid Composition– Cholesterol– Triglycerides (TGY)– Phospholipids

• Complexed with proteins to form “Lipoproteins”– Oil and water don’t mix!– Transport cholesterol &

TGY’s throughout the body – LDL, VLDL, HDL, etc.

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Page 6: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Major Lipoproteins

• LDL-c

• HDL-c

• VLDL-c– (i.e., TGY/5)

• IDL-c

• Chylomicrons

6Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

Page 7: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Lipoproteins

LDL, VLDL, IDL– Transport cholesterol in aqeuous media– All contain an apolipoprotein B subtype (ApoB)– Collectively represent the “atherogenic” components

HDL – Promotes reverse cholesterol transport from cells in

the vessel wall to the liver for disposal– Contain “atheroprotective” apolipoprotein A1 (ApoA1)

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Page 8: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Lipoproteins in atherosclerosis

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Page 9: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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CVDProgression

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Page 11: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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NCEP ATP IIIReleased: 2001

Page 12: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

NCEP ATP III Guidelines

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“LDL is the major atherogenic lipoprotein and has long been identified by NCEP as the primary target of cholesterol-lowering therapy”

“This focus on LDL has been strongly validated by recent clinical trials, which showthe efficacy of LDL-lowering therapy for reducing risk for CHD”

Page 13: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

NCEP ATP III Guidelines

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Page 14: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

CV biomarker shortfalls

• “Half of all myocardial infarctions and strokes occur despite apparently healthy men and women with LDL levels below currently recommended thresholds for treatment”1

• “Even with adequate LDL lowering, many patients on statin therapy have significant CVD risk”2

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1. Ridker PM, et al. Reduction in C-reactive protein and LDL cholesterol and CV events after initiation of rosuvastatin: a propective study of the JUPITER trial. Lancet. 2009:373: 1175-82.

2. Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22.

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Page 16: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22. 16

Page 17: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Emerging Risk Factors – ATP III excerpt

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Page 18: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Ideal new biomarker characteristics

• Can the biomarker be easily, precisely, and cost-effectively measured in a clinical setting?

• Are there available treatment strategies to positively alter the biomarker?

• Are the treatment strategies effective in reducing cardiovascular events?

18Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement for the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31: 811-22.

Page 19: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

New Cholesterol/CVD Biomarkers?• Non-HDL cholesterol• Apolipoproteins (Apo)

– Apolipoprotein A1 (ApoA1)– Apolipoprotein B (ApoB)– Apolipoprotein B/A1 ratio

• C-reactive Protein (CRP)• LDL particle size• Lipoprotein (a)• Lipoprotein-Associated Phospholipase A2

• Homocysteine

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Page 20: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Non-HDL Cholesterol

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Page 21: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 22: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Reasons non-HDL may be better than LDL

• non-HDL includes VLDL/TGY’s in risk equation– both LDL and TGY’s included

• Hypertriglyceridemia: – ↑ number of LDL particles (more atherogenic)– ↓ LDL size (small dense LDL are more atherogenic)– ↓ number of HDL particles (less anti-atherogenic)– ↓ HDL size (small dense HDL are less anti-atherogenic)

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Page 23: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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“In other words, because non-HDL cholesterol incorporates the 2 atherogenic components, it appears overall to be a better predictor of CHD risk than LDL cholesterol alone”

Page 24: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Non-HDL trials vs. LDL• Other studies demonstrating non-HDL as a better predictor

of future CVD events– Cui Y, et al. Arch Intern Med. 2001 – Bittner V, et al. Circulation. 2002– Von Muellen D, et al. Am J Cardiol. 2003– Lu W, et al. Diabetes Care. 2003– Farwell W, et al. Am J Cardiol. 2005– Ridker P, et al. JAMA. 2005– Liu J, et al. Diabetes Care. 2005 – Pischon T, et al. Circulation. 2005– Rallidis L, et al. Atherosclerosis. 2005– Liu J, et al. Am J Cardiol. 2006– Everett B, et al. J Am Coll Cardiol. 2006

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Page 25: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Non-HDL cholesterol

• Advantages

– Already available in lipid panel• lack of expense

– Easy calculation

– May not require a fasting state*• Emerging Risk Factors & INTERHEART trial

– Non-HDL goals are ↑30mg/dL than LDL goal

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Page 26: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Apolipoproteins

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Page 27: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Apolipoprotein B (ApoB)

• Where’s the evidence?

– ApoB is suggested to more accurately represent the total burden of atherogenic particles

– LDL-c underestimates CV risk due to small, dense LDL particles

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Page 28: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Apolipoproteins

28Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

Page 29: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 30: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

ApoB trials vs. LDL • Favor ApoB (vs. LDL-c)– Gotto A, et al. Circulation. 2000– Walldius G, et al. Lancet. 2001– Shai I, et al. Circulation. 2004– Ridker P, et al. JAMA. 2005– Pischon T, et al. Circulation. 2005– Everett B, et al. J Am Coll Cardiol. 2006– St. Pierre A, et al. Am J Cardiol. 2006– Hsia S, et al. Am J Cardiol. 2006– Ingelsson E, et al. JAMA. 2007– Benn M, et al. Arterioscler Thromb Vasc Biol. 2007

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Page 31: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

ApoB advantages

• More trials favor CV risk predictability with ApoB than LDL, especially in statin-treated patients

• ApoB is accurate in a non-fasting state

• Practical way to estimate ApoB?• calculate non-HDL cholesterol

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Page 32: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 33: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 34: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

LDL, non-HDL, and ApoB vs. CVDPost-hoc analysis of the TNT and IDEAL trials

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Post-hoc analysis of the TNT and IDEAL trials

Kastelein J, et al. Circulation 2008; 117:3002-9.

Page 35: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

INTERHEART study - July 2008 -

35McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33.

Page 36: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

INTERHEART results

36McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33.

ApoB

Non-HDL

HDL

ApoA1

Page 37: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

INTERHEART results

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Authors interpretation: non-fasting ApoB/ApoA1 was superior to any cholesterol ratio for estimation of risk of acute MI in all ethnic groups, in both sexes, and at all ages, and should be introduced into worldwide clinical practice

ApoB/ApoA1

TC/HDL

Page 38: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

The Emerging Risk Factors Collaboration - November 2009 -

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Page 39: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Emerging Risk Factors Collaboration - results

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Non-HDL

Apo B

Apo A1

HDL

Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

Page 40: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Emerging Risk Factors Collaboration

• Authors conclusions– CHD risk assessment: use either lipids or apolipoproteins – Should hinge on practical considerations (cost, availability)– Fasting lipid values (vs. non-fasting) offer little value

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Hazard Ratio 95% CILDL 1.38 1.09-1.73non-HDL 1.42 1.06-1.91ApoB/ApoA1 1.49 1.39-1.60non-HDL/HDL 1.50 1.38-1.62

Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

Page 41: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

C-Reactive Protein (hsCRP)

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Page 42: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

High sensitivity CRP

• Identified as a marker of underlying systemic inflammation

• Shown to independently predict future vascular events

• Can be reduced by statin therapy

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Page 43: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 44: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

< 1 mg/L 1 to 3 mg/L > 3 mg/L

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

PHS 1997 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland 2004

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

NHS 2004

HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS 2006

0

1

2

3

0

1

2

3

0

1

2

3

CHS 2005 PIMA 2005

Fully

Adj

uste

d Re

lativ

e Ri

sk

0

1

2

3

hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated

Page 45: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD CVD DeathDeathCABG/CABG/PTCAPTCA

JUPITERJUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Multi-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsRosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRPAmong Individuals With Low LDL and Elevated hsCRP

4-week 4-week run-inrun-in

Ridker PM. Rationale and design of the JUPITER study. Circulation 2003;108:2292-97.

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

Page 46: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo (251 / 8901)

Rosuvastatin (142 / 8901)

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulati

ve In

cide

nce

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Page 47: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

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Page 48: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

We certainly know nothing certain!!– Non-HDL and ApoB > LDL in CV risk prediction– Non-HDL > ApoB (but likely interchangeable)– Ratios appears better than single biomarkers– Non-HDL/HDL = ApoB/ApoA1 ratio > TC/HDL– Consider treating CRP with LDL (or whichever!)

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Summary

Page 49: Cardiovascular Risk Updates Cardiovascular Risk Updates USPHS Scientific and Training Symposium – Pharmacy Category May 25 th, 2010 LCDR Ryan Schupbach,

LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSLCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSPHS Claremore Indian HospitalPHS Claremore Indian Hospital

[email protected]@ihs.gov(918) 342-6455(918) 342-6455

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