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?
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
Inflammation- the missing link?
Inflammation- the missing link?
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
Inflammation- the missing link?
Inflammation- the missing link?
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
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%
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
Jupiter StudyJupiter Study
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
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
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
AFCAPS/TexCAPSAFCAPS/TexCAPS
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
AFCAPS/TexCAPSAFCAPS/TexCAPS
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.
Questions?Questions?