Should hsCRP be Included in the New Cardiovascular Guidelines?

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Should hsCRP be Included in the New Cardiovascular Guidelines? Controversy and Consensus in the JUPITER Trial Paul M Ridker, MD, MPH Eugene Braunwald Professor of Medicine Director, Center for Cardiovascular Disease Prevention Brigham and Women’s Hospital Harvard Medical School, Boston, MA USA Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

Paul M. Ridker, MD, MPH DISCLOSURES Consulting Fees Siemens USA, AstraZeneca, VBL Therapeutics, Schering-Plough Corp. / Merck & Co., Inc., and Novartis AG Grants/Contracted Research NHLBI, National Cancer Institute, American Heart Association, Donald W. Reynolds Foundation, Leduc Foundation, Doris Duke Charitable Foundation, AstraZeneca, Novartis AG, and sanofi-aventis U.S. LLC Dr. Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca.

LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006 LDLC (mg/dL) < 130 mg/dL 130-160 > 160 mg/dL < 3.4 mmol/L >4.1 mmol/L Sachdeva et al, Am Heart J 2009;157:111-7.e2.

hsCRP and Risk of Future MI and CVA in Apparently Healthy Men P Trend <0.001 Relative Risk of MI 1 2 3 4 P Trend <0.01 2 Relative Risk of Stroke 1 1 2 3 4 Quartile of hs-CRP Quartile of hs-CRP N Engl J Med 1997;336:973–979.

A Direct Comparison of LDL-C and hsCRP in the Prediction of First Ever Cardiovascular Events Among 27,939 Women Total Cardiovascular Events MI, CABG, PTCA Relative Risk Relative Risk Ischemic Stroke Cardiovascular Death Relative Risk Relative Risk N Engl J Med 2002;347:1557-65

hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated PHS 1997 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland 2004 NHS 2004 HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS 2008 CHS 2005 PIMA 2005 Fully Adjusted Relative Risk < 1 mg/L 1 to 3 mg/L > 3 mg/L

Coronary Heart Disease hsCRP concentration (mg/L) C-reactive protein concentration and risk of cardiovascular events : 2010 Coronary Heart Disease Ischaemic Stroke All Vascular Deaths 3.0 2.5 2.0 1.5 1.0 hsCRP concentration (mg/L) Risk ratio (95% CI) 0.5 4.0 8.0 Age, gender adjusted Fully adjusted Emerging Risk Factor Collaborators, Lancet 2010

Risk Ratio (95%CI) per 1-SD higher usual values C-reactive protein concentration and risk of cardiovascular events : 2010 Direct comparison of hsCRP, systolic blood pressure, total cholesterol, and non-HDLC Risk Ratio (95%CI) hsCRP Systolic BP Total cholesterol Non-HDLC 1.37 (1.27-1.48) 1.35 (1.25-1.45) 1.16 (1.06-1.28) 1.28 (1.16-1.40) 0.5 1.0 1.2 1.4 1.8 Risk Ratio (95%CI) per 1-SD higher usual values Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP Emerging Risk Factor Collaborators, Lancet 2010

www.reynoldsriskscore.org

Reynolds Risk Score – Example II Clinical Example: 72 year old non-diabetic woman, smoker, systolic BP 145 mm Hg, TC 216 mg/dL, HDLC 82 mg/dL, hsCRP 7.7 mg/L, and a positive family history for MI. Predicted 10-year risk Framingham Covariates: 6.9 percent Reynolds Covariates: 23.2 percent

Should our guidelines for vascular disease prevention change? Inflammation, hsCRP, and Vascular Prevention Is there evidence that individuals with elevated levels of the inflammatory biomarker hsCRP are at high vascular risk even when other risk factors are acceptable? Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received? Should our guidelines for vascular disease prevention change?

Inflammation, Statin Therapy, and hsCRP: Initial Observations P Trend = 0.005 -21.6% (P=0.004) 3 0.25 Placebo 0.24 2 0.23 0.22 Relative Risk Median hs-CRP (mg/dL) 0.21 1 Pravastatin 0.20 0.19 0.18 Pravastatin Placebo Pravastatin Placebo Baseline 5 Years Inflammation Absent Inflammation Present Circulation. 1998;98:839–844. Circulation. 1999;100:230-235.

Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy 0.0 0.5 1.0 1.5 2.0 2.5 0.00 0.02 0.04 0.06 0.08 0.10 Recurrent Myocardial Infarction or Coronary Death (percent) Follow-Up (Years) LDL > 70 mg/dL, CRP > 2 mg/L LDL > 70 mg/dL, CRP < 2 mg/L LDL < 70 mg/dL, CRP > 2 mg/L LDL < 70 mg/dL, CRP < 2 mg/L NEJM 2005;352:20-28.

Probability of Event-free Survival Primary Prevention : Whom Should We Treat ? 1.00 hsCRP < 2, LDL < 130 0.99 hsCRP < 2, LDL > 130 0.98 Probability of Event-free Survival hsCRP > 2, LDL < 130 0.97 hsCRP > 2, LDL > 130 0.96 0.00 2 4 6 8 Years of Follow-up N Engl J Med. 2002;347:1157-1165.

JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP MI Stroke Unstable Angina CVD Death CABG/PTCA Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) 4-week run-in 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

JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? AFCAPS/TexCAPS Low LDL Subgroups Low LDL, Low hsCRP Low LDL, High hsCRP Low LDL, Low hsCRP Low LDL, High hsCRP [A] [B] 0.5 1.0 2.0 0.5 1.0 2.0 RR Statin Effective Statin Not Effective Statin Effective Statin Not Effective While intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. New Engl J Med 2001;344:1959-65

Comparison of the JUPITER trial population to previous statin trials of primary prevention JUPITER WOSCOPS AFCAPS Sample size (n) 17,802 6,595 6,605 Women (n) 6,801 0 997 Minority (n) 5,118 0 350 Duration (yrs) 1.9 (max 5) 4.9 5.2 Diabetes (%) 0 1 6 Baseline LDL-C (mg/dL) 104 192 150 Baseline HDL-C (mg/dL) 49 44 36-40 Baseline TG (mg/dL) 118 164 158 Baseline hsCRP (mg/L) > 2 NA NA Intervention Rosuvastatin Pravastatin Lovastatin 20 mg 40 mg 10-40 mg JUPITER Trial Study Group, Am J Cardiol 2007; 100: 1659-1664

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death NEJM 2008;359:2195-2207 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Placebo 251 / 8901 0.08 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Fatal or Nonfatal Myocardial Infarction JUPITER Fatal or Nonfatal Myocardial Infarction NEJM 2008;359:2195-2207 Rosuvastatin Placebo - 55 % 1 2 3 4 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence HR 0.45, 95%CI 0.30-0.70 P < 0.0002

Fatal or Nonfatal Stroke JUPITER Fatal or Nonfatal Stroke NEJM 2008;359:2195-2207 0.030 HR 0.52, 95%CI 0.34-0.79 P = 0.002 0.025 Placebo 0.020 Cumulative Incidence 0.015 - 48 % 0.010 0.005 Rosuvastatin 0.000 1 2 3 4 Follow-up Years

- 47 % JUPITER Arterial Revascularization / Unstable Angina NEJM 2008;359:2195-2207 HR 0.53, 95%CI 0.40-0.70 P < 0.00001 0.06 Placebo (N = 143) 0.05 0.04 - 47 % Cumulative Incidence 0.03 0.02 Rosuvastatin (N = 76) 0.01 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158 Placebo 8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176

Total Venous Thromboembolism JUPITER Total Venous Thromboembolism HR 0.57, 95%CI 0.37-0.86 P= 0.007 0.025 0.020 Placebo 60 / 8901 0.015 - 43 % Cumulative Incidence 0.010 Rosuvastatin 34 / 8901 0.005 0.000 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 Placebo 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

Secondary Endpoint – All Cause Mortality JUPITER Secondary Endpoint – All Cause Mortality NEJM 2008;359:2195-2207 HR 0.80, 95%CI 0.67-0.97 P= 0.02 Placebo 247 / 8901 0.06 - 20 % 0.05 0.04 Cumulative Incidence 0.03 Rosuvastatin 198 / 8901 0.02 0.01 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

JUPITER Primary Endpoint – Understudied or “Low Risk” Subgroups NEJM 2008;359:2195-2207 Understudied Subgroups N HR (95%CI) Women 6,801 0.54 (0.37-0.80) Age > 70 5,695 0.61 (0.46-0.82) Black, Hispanic, Other 5,117 0.63 (0.41-0.98) “Low Risk” Subgroups Framingham Risk < 10 % 8,882 0.56 (0.38-0.83) 4,073 0.59 (0.40-0.87) BMI < 25 mg/m2 No Hypertension 7,586 0.62 (0.44-0.87) No metabolic Syndrome 10,296 0.49 (0.37-0.65) All Participants 17,802 0.56 (0.46-0.69) 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior

JUPITER: Primary Endpoint by Time Since Randomization P value 6 months 0.029 12 months <0.001 18 months <0.001 2 years <0.001 2.5 years <0.001 3 years <0.001 0.1 1 Hazard ratio (95% CI)

JUPITER Event Reduction at All Levels of Baseline LDLC < 130 mg/dL 0.20 0.5 1.0 2.0 4.0 Rosuvastatin Better Rosuvastatin Worse Baseline Levels LDLC < 100 mg/dL LDLC <90 mg/dL LDLC <80 mg/dL LDLC <70 mg/dL LDLC <60 mg/dL All Participants N 6,269 3,687 2,033 1,022 511 17,802

JUPITER Absolute Risk Reduction Increases With Increasing Levels of hsCRP 0.20 0.5 1.0 2.0 Better Worse Baseline hsCRP >10 mg/L _ >9 mg/L >8 mg/L >7 mg/L >6 mg/L >5 mg/L >4 mg/L >3 mg/L >2 mg/L N 2,503 3,071 3,839 4,723 5,897 7,425 9,726 12,939 17,802 3.0 4.0 5.0 Placebo Event Rate

JUPITER: Primary Endpoint According to Baseline Glucose Levels Normal Fasting Glucose Impaired Fasting Glucose HR 0.52 (95% CI 0.40-0.67) HR 0.66 (95% CI 0.47-0.93) 10 10 Placebo Placebo 8 8 6 6 Cumulative incidence, % 4 4 Rosuvastatin 2 Rosuvastatin 2 1 2 3 4 1 2 3 4 Years Years Of the 5572 individuals enrolled in JUPITER who were at high risk for developing diabetes due to impaired fasting glucose at study entry, the reduction in major CV events with rosuvastatin allocation was fully consistent with the trial as a whole. 29

Number Needed to Treat (5 year) JUPITER Number Needed to Treat (5 year) Endpoint All FRS<10 FRS>10 Primary Endpoint 25 47 17 Primary Endpoint, Mortality 22 39 16 MI, Stroke, CABG/PTCA, Death 23 42 16 MI, Stroke, Death 31 67 22 Benchmarks: Statins for hyperlipidemia 5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330

Full Adjusted Hazard Ratio JUPITER LDL reduction, hsCRP reduction, or both? Lancet 2009;373:1175-82 N Rate Placebo 7832 1.11 LDL>70mg/dL,hsCRP>2 mg/L 1384 1.11 LDL<70mg/dL,hsCRP>2 mg/L 2921 0.62 LDL>70mg/dL,hsCRP<2 mg/L 726 0.54 LDL<70mg/dL,hsCRP<2 mg/L 2685 0.38 LDL>70mg/dL,hsCRP>1 mg/L 1874 0.95 LDL<70mg/dL,hsCRP>1 mg/L 4662 0.56 LDL>70mg/dL,hsCRP<1 mg/L 236 0.64 LDL<70mg/dL,hsCRP<1 mg/L 944 0.24 P < 0.001 P < 0.001 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Better Rosuvastatin Worse Full Adjusted Hazard Ratio 0.21, 95% CI 0.09-0.52, P < 0.0001

Should our guidelines for vascular disease prevention change? Inflammation, hsCRP, and Vascular Prevention Is there evidence that individuals with elevated levels of the inflammatory biomarker hsCRP are at high vascular risk even when other risk factors are acceptable? Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received? Should our guidelines for vascular disease prevention change?

2009 Canadian Cardiovascular Society (CCS) Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult Primary Goal : LDLC High CAD, CVA, PVD <2mmol/L or 50% reduction Class I Most pts with Diabetes Level A FRS > 20 % RRS > 20 % Moderate FRS 10- 19 % <2mmol/L or 50 % reduction Class IIA RRS 10-19 % Level A LDL > 3.5 mmol/L TC/HDLC > 5.0 hsCRP > 2 in men >50 yr women > 60 yr Low FRS < 10 % <5mmol/L Class IIA Level A Secondary Targets : TC/HDLC < 4, non HDLC < 3.5 mol/L, hsCRP < 2 mg/L, TG < 1.7 mol/L, ApoB/A<0.8

FRS (%) Rosuvastatin Placebo HR (95%CI) JUPITER Primary Endpoint in “Intermediate Risk” Groups FRS (%) Rosuvastatin Placebo HR (95%CI) 5 – 10 % 32 (0.50) 59 (0.92) 0.55 (0.36-0.84) 10 – 20 % 74 (0.95) 145 (1.84) 0.51 (0.39-0.68) None of these patients are currently eligible to receive statin therapy because, using traditional risk factors alone and calculating Framingham 10-year risk, they are less than 20 % AND they already have untreated LDL-C levels below the treatment target in primary prevention (ie < 130 mg/dL). However, they ALL have hsCRP > 2 mg/L.

US FDA APPROVES NEW INDICATION FOR CRESTOR (ROSUVASTATIN CALCIUM) Approval based on JUPITER study which evaluated CRESTOR in a previously unstudied population For immediate release: 9 February 2009 The US Food and Drug Administration (FDA) has approved CRESTOR (rosuvastatin calcium) to reduce the risk of stroke, myocardial infarction (heart attack) and arterial revascularization procedures in individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease (CVD) based on age (men ≥50 and women ≥60), high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

Clinical Implications of the JUPITER Trial: Atherosclerotic Risk in Communities (ARIC) Men > 50, Women > 60, No Prior CVD, No JUPITER Exclusion LDL < 130 LDL < 130 CRP < 2 CRP > 2 N 1614 1621 LDL (mg/dL) 103 101 FRS (%) 5.0 4.7 CRP (mg/L) 0.9 4.7 CV Event 0.95 1.57 Rate/100py Wang et al, J Am Coll Cardiol 2009;54:2388–95)

Clinical Implications of the JUPITER Trial: Atherosclerotic Risk in Communities (ARIC) Men > 50, Women > 60, No Prior CVD, No JUPITER Exclusion LDL < 130 LDL > 130 LDL < 130 LDL > 130 CRP < 2 CRP < 2 CRP > 2 CRP > 2 N 1614 1132 1621 1146 LDL (mg/dL) 103 155 101 156 FRS (%) 5.0 6.3 4.7 7.1 CRP (mg/L) 0.9 1.0 4.7 4.4 CV Event 0.95 1.22 1.57 2.19 Rate/100py Wang et al, J Am Coll Cardiol 2009;54:2388–95)

Clinical Relevance of hsCRP in the CORONA Trial : Identifying a High Risk CHF Population That Benefits From Statin Therapy Primary Endpoint hsCRP < 2 mgL hsCRP > 2 mg/L P-value 0.5 0.02 Total Mortality hsCRP < 2 mgL hsCRP > 2 mg/L 0.2 0.05 Coronary Endpoint hsCRP < 2 mgL hsCRP > 2 mg/L 0.3 0.017 Hosp. Worsening CHF hsCRP < 2 mgL hsCRP > 2 mg/L 0.4 0.009 Morality/HF Hosp. hsCRP < 2 mgL hsCRP > 2 mg/L 0.3 0.006 0.5 1.0 1.5 Rosuvastatin Superior Rosuvastatin Inferior McMurray JV et al, Circulation 2009;2188-2196

Public Health Implications JUPITER Public Health Implications Exercise, diet, and smoking cessation remain the first interventions for those with elevated LDLC or hsCRP. However, application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone. Simplified guidelines that advocate combined lifestyle and pharmacologic therapy in those groups where trial evidence clearly supports a net benefit have the potential to greatly improve patient care and public health. With thanks to the 17,802 patients and the >1,000 physicians worldwide for their effort and commitment to the JUPITER trial program.

Public Health Implications JUPITER Public Health Implications Low LDL, Low hsCRP Low LDL, High hsCRP Low LDL, Low hsCRP Low LDL, High hsCRP [A] [B] 0.5 1.0 2.0 New Engl J Med 2001;344:1959-65 0.5 1.0 2.0 RR Statin Effective Statin Not Effective We must rely on hard clinical trial evidence to inform clinical guidelines and compute cost-effectiveness. Making assumptions about the net benefit to risk ratio for statins in specific patient groups where contradicting data exist (such as those with low LDLC and low hsCRP) is unwarranted and will lead to claims that we are promoting pharmaceutical use in the absence of evidence.