Reduction of C-Reactive Protein for the Prevention of CHD Jillian Moser EBM Presentation February 25, 2009 Jillian Moser EBM Presentation February 25,

Reduction of C-Reactive Protein for the

Prevention of CHD

Reduction of C-Reactive Protein for the

Prevention of CHD

Jillian MoserEBM PresentationFebruary 25, 2009

Jillian MoserEBM PresentationFebruary 25, 2009

The Facts…The Facts…Coronary Heart Disease accounts for

approximately 1/3 of all deaths worldwide.Over 80 million Americans (1 in 3 adults)

have some form of CHD.Nearly 2,400 Americans die daily from

cardiovascular disease, 1 every 37 seconds.

-American Heart Association

Coronary Heart Disease accounts for approximately 1/3 of all deaths worldwide.

Over 80 million Americans (1 in 3 adults) have some form of CHD.

Nearly 2,400 Americans die daily from cardiovascular disease, 1 every 37 seconds.

-American Heart Association

What you may not know…What you may not know…

1/2 of all acute myocardial infarctions and strokes occur in individuals with LDL cholesterol levels below currently recommended thresholds for treatment.

So what are we missing???

1/2 of all acute myocardial infarctions and strokes occur in individuals with LDL cholesterol levels below currently recommended thresholds for treatment.

So what are we missing???

Inflammation- the missing link?


Atherosclerosis is a complex disease not solely dependent on the accumulation of lipids in vessel walls.

It is initiated by injury to the endothelial cells lining arterial walls, promoting the release of inflammatory mediators

hs-CRPInterleukin-6Tumor necrosis factor

Atherosclerosis is a complex disease not solely dependent on the accumulation of lipids in vessel walls.

It is initiated by injury to the endothelial cells lining arterial walls, promoting the release of inflammatory mediators

hs-CRPInterleukin-6Tumor necrosis factor

PathophysiologyPathophysiology

Insult to vessel wall generation of immunologic factors stimulate CRP secretion

opsonization of injured and foreign cellsattraction of macrophages inflammatory

response local decrease in nitric oxide production decreased vasodilation

decreased myocyte perfusion myocardial ischemia

Insult to vessel wall generation of immunologic factors stimulate CRP secretion

opsonization of injured and foreign cellsattraction of macrophages inflammatory

response local decrease in nitric oxide production decreased vasodilation

decreased myocyte perfusion myocardial ischemia



High sensitivity C-reactive protein (hs-CRP) is an inflammatory marker found in bloodProduced by the liver and fat cellsAn acute-phase reactant- levels rise

dramatically during inflammatory process

Binds to foreign and damaged cells to enhance phagocytosis by macrophages

Indicate the presence of active vascular inflammation and atherosclerosis

High sensitivity C-reactive protein (hs-CRP) is an inflammatory marker found in bloodProduced by the liver and fat cellsAn acute-phase reactant- levels rise

dramatically during inflammatory process

Binds to foreign and damaged cells to enhance phagocytosis by macrophages

Indicate the presence of active vascular inflammation and atherosclerosis



A hs-CRP level >2.4 mg/L has been associated with a doubled risked of a coronary event compared to levels below 1 mg/L

To measure the CRP level, a hs-CRP is used: this is an automated blood test designed for greater accuracy in measuring low levels of CRP

Aides the provider in assessing cardiovascular riskLow-risk <1 mg/LModerate-risk 1-3 mg/LHighest-risk >3 mg/L

A hs-CRP level >2.4 mg/L has been associated with a doubled risked of a coronary event compared to levels below 1 mg/L

To measure the CRP level, a hs-CRP is used: this is an automated blood test designed for greater accuracy in measuring low levels of CRP

Aides the provider in assessing cardiovascular riskLow-risk <1 mg/LModerate-risk 1-3 mg/LHighest-risk >3 mg/L

While Statin therapy has shown efficacy for LDL cholesterol reduction, emerging data suggests that statins reduce inflammation and CRP levels as well

Mechanisms unknown

The statin-mediated reduction of CRP is independent of the LDL reduction effect of the drug

Elevated levels of hs-CRP have shown to be a strong predictor of future cardiovascular events in several studies.

While Statin therapy has shown efficacy for LDL cholesterol reduction, emerging data suggests that statins reduce inflammation and CRP levels as well

Mechanisms unknown

The statin-mediated reduction of CRP is independent of the LDL reduction effect of the drug

Elevated levels of hs-CRP have shown to be a strong predictor of future cardiovascular events in several studies.

So what does this mean?So what does this mean?The current NCEP guidelines for preventative

treatment of CVD may need a revision…Recently, several studies have hypothesized

using statins for the reduction of cardiovascular disease in individuals with high levels of CRP but without overt hyperlipidemia.

The current NCEP guidelines for preventative treatment of CVD may need a revision…

Recently, several studies have hypothesized using statins for the reduction of cardiovascular disease in individuals with high levels of CRP but without overt hyperlipidemia.

Current National Cholesterol Education Program (NCEP) guidelines for treatment

of hyperlipidemia

Current National Cholesterol Education Program (NCEP) guidelines for treatment

of hyperlipidemia

The Adult Treatment Panel III Guidelines

Risk Category LDL Goal

LDL Level at Which to Initiate Therapeutic Lifestyle Changes

LDL Level at Which to Consider Drug Therapy

CHD or CHD Risk Equivalents (10-year risk >20%) <100 mg/dL >100 mg/dL

130 mg/dL (100-129 mg/dL: drug optional)

2+ Risk Factors (10-year risk less than or equal to20%) <130 mg/dL >130 mg/dL

10-year risk 10-20%: >130 mg/dL

10-year risk <10%: >160 mg/dL

0-1 Risk Factor <160 mg/dL >160 mg/dL

>190 mg/dL(160-189 mg/dL: LDL-lowering drug optional)

Risk % determined by Framingham Point Scores

http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm

The big question…The big question…

P- Adult patients with borderline hyperlipidemia and elevated hs-CRP

I- Aggressive cholesterol control via Statin therapy C- Cholesterol control via lifestyle modifications O- Reduction in the development of CAD

In adult patients presenting with an elevated high sensitivity C-reactive protein level in addition to borderline hyperlipidemia, does aggressive cholesterol control via Statin therapy offer a greater reduction in the development of coronary artery disease when compared to cholesterol control via lifestyle modifications?

P- Adult patients with borderline hyperlipidemia and elevated hs-CRP

I- Aggressive cholesterol control via Statin therapy C- Cholesterol control via lifestyle modifications O- Reduction in the development of CAD

In adult patients presenting with an elevated high sensitivity C-reactive protein level in addition to borderline hyperlipidemia, does aggressive cholesterol control via Statin therapy offer a greater reduction in the development of coronary artery disease when compared to cholesterol control via lifestyle modifications?

JUPITER studyJUPITER study Study hypothesis: People with elevated hs-CRP

levels but without overt hyperlipidemia might benefit from statin treatment

Randomized, double-blind, placebo-controlled 17,802 health men and women: LDL cholesterol

levels <130mg/dL and hs-CRP >2.0mg/dL Treatment: 1/2 received Rosuvastatin 20mg, 1/2

received placebo Measurement: occurrence of “endpoint”

MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes

Study hypothesis: People with elevated hs-CRP levels but without overt hyperlipidemia might benefit from statin treatment

Randomized, double-blind, placebo-controlled 17,802 health men and women: LDL cholesterol

levels <130mg/dL and hs-CRP >2.0mg/dL Treatment: 1/2 received Rosuvastatin 20mg, 1/2

received placebo Measurement: occurrence of “endpoint”

MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes

JUPITER StudyJUPITER Study

The Results:Rosuvastatin reduced LDL cholesterol by 50%Rosuvastatin reduced hs-CRP levels by 37%Rosuvastatin reduced endpoint occurrences by 57%

Trial Conclusion: Apparently healthy persons without hyperlipidemia but with elevated hs-CRP levels would benefit from Rosuvastatin therapy for the prevention of major cardiovascular events

The Results:Rosuvastatin reduced LDL cholesterol by 50%Rosuvastatin reduced hs-CRP levels by 37%Rosuvastatin reduced endpoint occurrences by 57%


Jupiter StudyJupiter Study



Rate of Cardiovascular Events: Rosuvastatin vs. Placebo

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Rate

r p

er

10

0 p

ers

on

s

Placebo

Rosuvastatin

AFCAPS/TexCAPSAFCAPS/TexCAPS

Both of initial studies demonstrated statins reduce the risk of first coronary events in hyperlipidemic individuals

A sub-study was conducted to evaluate the effect of Lovastatin 40mg on hs-CRP values and rate of cardiovascular events

5-year randomized, double-blind, placebo-controlled with 5742 participants

Measurements: hs-CRP values and endpoint occurrences

Both of initial studies demonstrated statins reduce the risk of first coronary events in hyperlipidemic individuals

A sub-study was conducted to evaluate the effect of Lovastatin 40mg on hs-CRP values and rate of cardiovascular events

5-year randomized, double-blind, placebo-controlled with 5742 participants

Measurements: hs-CRP values and endpoint occurrences


The Results:Lovastatin therapy reduced CRP level by

14.8%Lovastatin was effective in reduction of

coronary events in participants with hyperlipidemia and elevated CRP AND in participants without hyperlipidemia but elevated CRP

Note: Lovastatin was found to be ineffective in the reduction of events in participants who had neither hyperlipidemia or elevated CRP

The Results:Lovastatin therapy reduced CRP level by

14.8%Lovastatin was effective in reduction of

coronary events in participants with hyperlipidemia and elevated CRP AND in participants without hyperlipidemia but elevated CRP

Note: Lovastatin was found to be ineffective in the reduction of events in participants who had neither hyperlipidemia or elevated CRP


The Conclusion: Lovastatin therapy is also effective for primary prevention of coronary events among persons without elevated lipid levels but with elevated CRP

The Conclusion: Lovastatin therapy is also effective for primary prevention of coronary events among persons without elevated lipid levels but with elevated CRP

Rate of Acute Coronary Events: Lovastatin vs. Placebo

0

0.01

0.02

0.03

0.04

0.05

0.06

Elevated LDLand elevated

CRP

Elevated LDLand normal

CRP

Normal LDLand elevated

CRP

Normal LDLand normal

CRP

Rate

of

Even

ts

Placebo Group: Rate ofEvents

Lovastatin Group:Rateof Events

WOSCOPS, PRINCE, MIRACL, REVERSAL, and

CURVES trials

WOSCOPS, PRINCE, MIRACL, REVERSAL, and

CURVES trials

Original studies that investigated the reduction of hs-CRP in hyperlipidemic patients via statin therapy

Original studies that investigated the reduction of hs-CRP in hyperlipidemic patients via statin therapy

Dietary vs. StatinDietary vs. Statin

Diet has traditionally been advocated before drugs to prevent cardiovascular disease

In general, cholesterol reduction via diet is small compared to drug therapy

Yet, due to most peoples disdain for taking pills and the side-effects that may come with taking them, dietary role in CHD reduction deserves consideration

Diet has traditionally been advocated before drugs to prevent cardiovascular disease

In general, cholesterol reduction via diet is small compared to drug therapy

Yet, due to most peoples disdain for taking pills and the side-effects that may come with taking them, dietary role in CHD reduction deserves consideration

Dietary vs. StatinDietary vs. Statin

Hypothesis: If CRP reduction has been demonstrated through statin therapy, a cholesterol lowering diet may also lower CRP levels

34 healthy hyperlipidemic participants completed a 3 phase randomized crossover trial

1. Control2. Statin3. Dietary portfolio

hs-CRP measurements at weeks 0, 2, and 4

Hypothesis: If CRP reduction has been demonstrated through statin therapy, a cholesterol lowering diet may also lower CRP levels

34 healthy hyperlipidemic participants completed a 3 phase randomized crossover trial

1. Control2. Statin3. Dietary portfolio

hs-CRP measurements at weeks 0, 2, and 4

Dietary vs. StatinDietary vs. StatinAll food was provided and all diets were

vegetarian1. Control: low-saturated-fat dairy, whole wheat

bread and cereal, fruits, and vegetables2. Statin: same as control diet plus Lovastatin 20 mg3. Portfolio: 1.0 g plant sterols per 1000 kcal of

diet in a plant sterol ester enriched margarine, 9.8 g viscous fivers per 1000 kcal of diet from

oats, barley, and psyllium, 21.4 g soy protein per 1000 kcal as soy milk and soy meat analogues, and 14 g whole almonds per 1000 kcal of diet

All food was provided and all diets were vegetarian

1. Control: low-saturated-fat dairy, whole wheat bread and cereal, fruits, and vegetables

2. Statin: same as control diet plus Lovastatin 20 mg3. Portfolio: 1.0 g plant sterols per 1000 kcal of

diet in a plant sterol ester enriched margarine, 9.8 g viscous fivers per 1000 kcal of diet from

oats, barley, and psyllium, 21.4 g soy protein per 1000 kcal as soy milk and soy meat analogues, and 14 g whole almonds per 1000 kcal of diet

Dietary vs. StatinDietary vs. StatinResults:

Patients lost a similar amount of weight on all three treatments

The CRP reduction at 4 weeks was significant for both statin and portfolio, but not for control

Statin and portfolio were deemed equally effective Statin CRP reduction: 16.3% Portfolio CRP reduction: 23.8%

Conclusion: A diet that has been shown to be effective in lowering serum cholesterol also lowers CRP to the same extent as a statin when taken by the same individuals

The study did not investigate prevention of CHD

Results:Patients lost a similar amount of weight on all three

treatmentsThe CRP reduction at 4 weeks was significant for both

statin and portfolio, but not for controlStatin and portfolio were deemed equally effective

Statin CRP reduction: 16.3% Portfolio CRP reduction: 23.8%

Conclusion: A diet that has been shown to be effective in lowering serum cholesterol also lowers CRP to the same extent as a statin when taken by the same individuals

The study did not investigate prevention of CHD

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Mean CRP reduction at week

0, 2, and 4

Recap of study resultsRecap of study results

Trial Statin CRP

reduction End point reduction

WOSCOPS Pravastatin 40mg *not measured 31%

PRINCE Pravastatin 40mg 16.90% *not measured

AFCAPS/TexCAPS study Lovastatin 40mg 14.80% 33%

MIRACL Atorvastatin 80mg 83% 85%

CURVES Atorvastatin 10mg 38% 28.30%

REVERSAL Atorvastatin 80mg 36.40% *not measured

JUPITER Rosuvastatin 20mg 37% 57% Dietary vs. Statin Lovastatin 40mg 16.30% *not measured Profile diet 28.30%

Patient ExamplePatient Example

61 y/o female with PMH of hyperlipidemia, on Atorvastatin 20mg daily

LDL cholesterol level of 113 mg/dLhs-CRP level of 7.1 mg/L

Patient’s Atorvastatin increased to 40mg daily, labs rechecked in 4 mo.

LDL cholesterol 97 mg/dLhs-CRP 0.8 mg/L

61 y/o female with PMH of hyperlipidemia, on Atorvastatin 20mg daily

LDL cholesterol level of 113 mg/dLhs-CRP level of 7.1 mg/L

Patient’s Atorvastatin increased to 40mg daily, labs rechecked in 4 mo.

LDL cholesterol 97 mg/dLhs-CRP 0.8 mg/L

ConclusionsConclusions Inflammation, indicated by biomarkers such

as hs-CRP, is a risk factor for cardiovascular disease

BOTH statin therapy and therapeutic lifestyle changes that have been proven to reduce LDL cholesterol also reduce CRP

Reduction of CRP levels reduces the occurrence of heart attacks, strokes, hospitalizations for unstable angina, arterial revascularizations, and deaths from cardiovascular causes

Inflammation, indicated by biomarkers such as hs-CRP, is a risk factor for cardiovascular disease

BOTH statin therapy and therapeutic lifestyle changes that have been proven to reduce LDL cholesterol also reduce CRP

Reduction of CRP levels reduces the occurrence of heart attacks, strokes, hospitalizations for unstable angina, arterial revascularizations, and deaths from cardiovascular causes

ConclusionsConclusionsIn adult patients presenting with an elevated highsensitivity C-reactive protein level in addition to borderline hyperlipidemia, does aggressive cholesterol control via Statin therapy offer a greater reduction in the development of coronary artery disease when compared to cholesterol control via lifestyle modifications?

Both dietary/lifestyle modifications AND statin offer significant reduction in hs-CRP and development of coronary artery disease

Neither dietary nor statin therapy is superior over the other

In adult patients presenting with an elevated highsensitivity C-reactive protein level in addition to borderline hyperlipidemia, does aggressive cholesterol control via Statin therapy offer a greater reduction in the development of coronary artery disease when compared to cholesterol control via lifestyle modifications?

Both dietary/lifestyle modifications AND statin offer significant reduction in hs-CRP and development of coronary artery disease

Neither dietary nor statin therapy is superior over the other

ApplicationApplication

Measurement of hs-CRP should be incorporated into routine blood work when determining a patients risk factors for cardiovascular disease

Patients with normal or borderline high cholesterol levels but elevated hs-CRP should be treated with therapeutic lifestyle changes or a statin for prevention of cardiovascular events

Measurement of hs-CRP should be incorporated into routine blood work when determining a patients risk factors for cardiovascular disease

Patients with normal or borderline high cholesterol levels but elevated hs-CRP should be treated with therapeutic lifestyle changes or a statin for prevention of cardiovascular events

ReferencesReferences Ridker, P.M., Danielson, E., Fonseca, F. , Genest, J., & Gotto, A.M.

(2008). Rosuvastatin to prevent vascular events in med and women with elevated c-reactive protein. The New England Journal of Medicine, 359, 2195-2207.

Jenkins, D.J., Kendall, C.W., Faulkner, D.A., & Josse, A.R. (2005). Direct comparison of dietray portfolio vs statin on c-reactive protein. European Journal of Clinical Nutrition, 59, 851-860.

Elliott, W.T. (2009, January). JUPITER: C-reactive protein a marker for CV events?. Pharmacology Watch, 1-2.

Chan, K.Y., Boucher, E.S., Gandhi, P.J., & Silvia, M.A. (2004). HMG-CoA reductase inhibitors for lowering elevated levels of c-reactive protein. American Journal of Health-System Pharmacy, 61, 1676-1681.

Ridker, P.M., Rifai, N., Clearfield, M., Downs, J.R., Weis, S.E., & Miles, J.S. (2001). Measurement of c-reactive protein for the targeting of statin therapy in the primary prevention of acute cornary events. The New England Journal of Medicine, 344, 1959-1965.

Ridker, P.M., Danielson, E., Fonseca, F. , Genest, J., & Gotto, A.M. (2008). Rosuvastatin to prevent vascular events in med and women with elevated c-reactive protein. The New England Journal of Medicine, 359, 2195-2207.

Jenkins, D.J., Kendall, C.W., Faulkner, D.A., & Josse, A.R. (2005). Direct comparison of dietray portfolio vs statin on c-reactive protein. European Journal of Clinical Nutrition, 59, 851-860.

Elliott, W.T. (2009, January). JUPITER: C-reactive protein a marker for CV events?. Pharmacology Watch, 1-2.

Chan, K.Y., Boucher, E.S., Gandhi, P.J., & Silvia, M.A. (2004). HMG-CoA reductase inhibitors for lowering elevated levels of c-reactive protein. American Journal of Health-System Pharmacy, 61, 1676-1681.

Ridker, P.M., Rifai, N., Clearfield, M., Downs, J.R., Weis, S.E., & Miles, J.S. (2001). Measurement of c-reactive protein for the targeting of statin therapy in the primary prevention of acute cornary events. The New England Journal of Medicine, 344, 1959-1965.

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Reduction of C-Reactive Protein for the Prevention of CHD Jillian Moser EBM Presentation February 25, 2009 Jillian Moser EBM Presentation February 25,