Beyond LDL

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Beyond LDL

• Novel Biochemical Markers of Cardiovascular Risk

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Why should I care?
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Your Patients Know

• U.S News and World Report November 25, 2002
• Cover Story
• The Heart Test That Could Save Your Life
• An easy, new way to help predict your risk of
  heart attack and stroke

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New Practice Guidelines by CDC/AHA
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• Missing High Risk Patients
• 77 of cardiovascular events,
• LDL lt160
• 46 of cardiovascular events,
• LDL lt130

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Potential Markers

• Inflammatory
• hs-CRP, IL-6, IL-18
• Fibrinogen
• sICAM-1
• TNF-a, SAA, MPO, sCD40
• Oxidized LDL
• GPX1 activity
• Nitrotyrosine
• Homocysteine
• Cystatin-C
• Coagulation
• tPA, PAI-1
• Fibrinogen
• D-dimer
• Von Willebrand Factor

• Lipid Markers
• Lipid Profile
• Small dense LDL
• Oxidized LDL
• LDL Particle No.
• HDL profiles
• Lp(a)
• ApoB/ApoA-1
• VAP
• Natriuretic Peptides
• BNP
• N-terminal proBNP
• ADMA
• MMP-9
• TIMP-1

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Where to Begin?
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Case 1
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• 56yo female
• smoker
• untreated HTN (BP 142/85)
• TC 220, HDL 35, LDL 125
• Do you treat her?

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Framingham Risk

• Calculating 10yr Risk
• 55-59 yrs 8 pts
• TC 200-239 4 pts if 50-59
• Smoker 4 pts if 50-59
• HDL lt40 2
• SBP 140-159 untreated 3 pts
• TOTAL 21 pts or 14 10 yr risk
• Recommendations for 10-20 10-yr risk?

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10-20 10 year risk

• Intermediate Risk ? Moderately High Risk
• Pharmacotherapy
• LDLgt160, maybe 130
• 2004 Option to initiate at 100-129 if more
  concerning risk factors

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High Sensitivity C-Reactive Protein
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What is hs-CRP

• CRPacute phase reactant
• hs-CRPbaseline CRP levels (inflammatory
  predilection)
• lt1 low risk
• 1-3 average risk
• gt3 high risk
• Standardized test nationwide
• 62.50

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Practice Guidelines

• AHA/CDC Scientific Statement January 28, 2003
• Measurement of hs-CRP is an independent
  marker of risk and may be used at the discretion
  of the physician as part of global coronary risk
  assessment in adults without known cardiovascular
  disease. Weight of evidence favors use
  particularly among those judged at intermediate
  risk by global risk assessment.

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Evidence

• Up through 2004
• 19 large scale prospective studies
• Independent risk predictor
• Better than LDL at predicting CV risk
• Predicts risk of metabolic syndrome
• Predicts 14 day MI/mortality in CP pts.

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Recent hs-CRP Research

• Since 2005
• Mixed results
• Not independent risk predictor
• Increased risk attributable to traditional risk
  factors that parallel hs-CRP

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The Final Answer on hs-CRP

• Evidence that lowering hs-CRP decreases
  cardiovascular events and mortality limited
• JUPITER Trial
• 15,000 patient RCT
• low LDL but high hs-CRP
• Statins
• Enrollment 2003

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Are there effective treatments to lower hs-CRP?

• Diet, wt loss, exercise, smoking cessation
• Statins
• Beta-blockers
• ACE inhibitors
• Fibrates
• Niacin
• Rosiglitazone in DM2
• ASA (56 fewer events)

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How Could I Incorporate hs-CRP in My Practice?

• Moderately High Risk Patients
• (10yr Framingham Risk of 10-20)
• Dilemma over whether to treat
• Add hs-CRP to lipid profile
• hs-CRP gt3, high risk
• Begin Statin therapy

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Apolipoprotein B

• ApoB

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Pathophysiology

• Apolipoprotein B found on all the atherogenic
  lipoproteins LDL, IDL, VLDL, Lp(a)
• Reflects total of Atherogenic lipoproteins
• ApoA-1 found on HDL
• ApoB/ApoA-1 ratio

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Evidence

• Conflicting results
• 175,000 ApoB better than LDL
• 12,000 ApoB added no benefit over LDL, HDL,
  Lp(a), TGs(in women)

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Using ApoB to Assess CV Risk

• High Risk gt 120
• Treatment Target lt80
• Statins
• Fasting, 70.75

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Monitoring Effectiveness of Treatment

• On Treatment ApoB reflects new risk level

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Recommendations

• AHA does not recommend testing
• Canadian national guidelines have recommended
  testing since 2001
• March 2006 Journal of Internal Medicine
• 10 country panel
• ApoB should be included in all guidelines

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Lipoprotein (a)

• Lp(a)

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Lipoprotein (a)

• Type of LDL bound to ApoB and Apo(a)
• Prothrombotic
• Binding domain similar to plasminogen, may
  compete, favoring thrombosis
• Proatherogenic
• preferentially binds oxidized phospholipids and
  taken up into atheromatous plaques

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Risk Factors

• Not associated with most traditional risk factors
• Smoking
• BMI
• Hypertension
• Cholesterol subfractions
• Exercise and dieting have no effect
• Associated with Diabetes mellitus and
  postmenopausal state

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Evidence

• Conflicting
• PHS, Helsinki Heart and Quebec CV Studies fail to
  find association between Lp(a) CV dz
• 2 Large Metanalysis show association
• Danesh et al. - 27 studies, 10 yrs f/u,
  combined risk ratio of 1.6 (top 1/3 vs bottom
  1/3)

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When to Consider?

• 1. Premature CV dz w/o risk factors
• 2. Strong FH of premature CV dz
• 3. Resistent Hyperlipidemia
• 4. Hypertension, evidence of early end organ
  damage

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Whats Significant

• CMS
• Lp(a) gt 30 with TChol/HDL gt 5.5
• Greater than 90th percentile
• 39 in men
• 39.5 in women
• Higher in blacks

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How to Treat?

• Unresponsive to statins, bile resin sequestrants,
  fibric acid derivatives
• If high risk based on Lp(a)
• Target dropping LDL with statin
• If cannot reach target, consider Nicotinic Acid
• Omega-3 fatty acids, moderate EtOH, Estrogen

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Homocysteine
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Metanalysis

• MI 1.7 OR
• Stroke 2.5 OR
• PAD 6.8 OR
• Folate, B12, B6

• 15 studies
• 9 studies
• 5 studies

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AHA Recommendation

• Screening for homocysteine may be useful in
  patients with a personal or family history of
  cardiovascular disease, but in whom the
  well-established risk factors (smoking, high
  blood cholesterol, high blood pressure, physical
  inactivity, obesity and diabetes) dont exist.

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Hope-2, NEJM April 13, 2006

• Affects of Folic Acid/B6/B12 vs placebo
• Homocysteine levels
• Outcomes CV death, MI, stroke
• Population gt55yrs with Vascular dz or DM
• 5522 pts
• 5 year f/u
• Over 1000 events

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Results

• CV death RR 0.96 (CI 0.81-1.13)
• MI RR 0.98 (CI 0.85-1.14)
• Stroke RR 0.75 (CI 0.59-0.97)
• Unstable Angina RR 1.24 (CI 1.04-1.49)

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Conclusion

• No HOPE for Homocysteine

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Evidenced Based Recommendation

• Institute for Clinical Systems Improvement
• Folic Acid and B vitamins are not recommended
  for the treatment of hyperhomocysteinemia or the
  prevention of Coronary Artery Disease (2006)

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BNP

• NT-proBNP

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B-type Natriuretic PeptideBNP

• CHF
• Acute Coronary Syndromes
• Risk of Death s/p MI
• Prediction of cardiovascular events in
  asymptomatic individuals

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JAMA Apr 6, 2005

• NT-pro BNP, CRP urinary albumin
• Population older adults (50-89)
• Outcomes mortality and 1st CV events

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Adjusted Results
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Significant Details

• NT-proBNP only predictor of stroke
• 3.63 fold increase risk
• Older Adults

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Circulation July 5, 2005

• NT-proBNP, CRP, renin
• Population previous stroke or TIA
• Outcomes MI

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Highest to Lowest Quartile
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Conclusion

• After adjusting for traditional risk factors only
  BNP and Renin remain independent risk factors

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NT-proBNPs RoleIn Screening for Risk of CV
Events

• Promising Results
• Research still early
• Unanswered Questions
• Whom to test
• What values are significant
• What do you do about it

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Case 2

• 62yo male f/u MI
• HTN, Hyperlipidemia
• Father MI 50, brother 60, sister 50, sister 38
• Angioplasty 1995, 4 Stents 2003
• Meds simvastatin 80mg, atenolol 25mg,
  telmisartan 20mg, clopidogrel 75mg, ASA 81mg

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What would you do?

• BP 124/76
• Lipid panel
• LDL 114
• HDL 29
• TG 241
• Gluc 107
• Atorvastatin 80mg
• Cardiac Rehab, Dietician, Fish oil
• Ezetimibe 10 mg

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Response

• Lipids
• TC 122
• LDL 64
• TG 114
• HDL 31
• Gluc 114
• Hs-CRP 6.9
• ApoB 74
• Lp(a) 62
• Homocysteine 13.1

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What else?

• Niacin
• Metformin
• CRP 6.9 ? 3.9

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Whats Ready for Use in Patient Care?
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Strategy in the Shadowlands

• Screen with TC and HDL
• Evidence based recommendation
• USPSTF
• If high risk, repeat with LDL and TGs
• If gt2 risk factors, calculate Framingham Risk
• If warrants treatment, treat

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Strategy in the Shadowlands

• If not, consider hs-CRP or ApoB in moderately
  high risk group.
• ApoB to monitor effectiveness of tx.
• Lp(a) if personal or family history of premature
  CAD w/o traditional risk factors, resistent
  hyperlipidemia or premature end-organ damage in
  hypertensive patients.
• Stay tuned
• ApoB hsCRP have potential for universal
  screening
• BNP looks promising but more study needed.

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