Latest Insights from the JUPITER Study John J.P. Kastelein MD PhD Professor of Medicine Dept. of Vascular Medicine Academic Medial Center / University of Amsterdam
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?
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 5 5 4 4 3 3 2 2 1 1 0 1 2 3 4 5 0 1 2 3 4 5 Ischemic Stroke Cardiovascular Death 5 5 4 4 3 3 2 2 1 1 0 1 2 3 4 5 0 1 2 3 4 5 N Engl J Med 2002;347:1557-65
The net reclassification improvement when CRP was added to traditional risk factors was 11.8 % for hard CHD (P=0.009), a value greater than that of LDL, HDL, or blood pressure in the Framingham Data Wilson P, et al Circ Cardiovasc Qual Outcomes 2008;1:92-97
Meta-analysis of 54 Prospective Cohort Studies: The magnitude of independent risk associated with hscrp is at least as large, if not larger, than that of BP and cholesterol 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 January 2010 CR-5
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?
Cumulative Rate of Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy Recurrent Myocardial Infarction or Coronary Death (percent) 0.00 0.02 0.04 0.06 0.08 0.10 0.00 0.02 0.04 0.06 0.08 0.10 LDLC>70 mg/dl LDLC<70 mg/dl hscrp>2 mg/l hscrp<2 mg/l 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 NEJM 2005;352:20-28. Follow-Up (years)
REVERSAL: Regression of Atherosclerosis On Statin Therapy Occurs Primarily Among Those with Both LDL and CRP Reduction 10 8 +8mm 3 6 4 2 +2mm 3 0-2 - 1mm 3-2mm 3-4 LDL CRP LDL CRP LDL CRP LDL CRP Nissen / Ganz NEJM 2005; 352:29-38
Probability of Event-free Survival Primary Prevention : Whom Should We Treat? 1.00 0.99 hscrp < 2, LDL < 130 0.98 0.97 hscrp < 2, LDL > 130 hscrp > 2, LDL < 130 0.96 hscrp > 2, LDL > 130 0.00 0 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 No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA 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 Baseline Clinical Characteristics Rosuvastatin Placebo (N = 8901) (n = 8901) Age, years (IQR) 66.0 (60.0-71.0) 66.0 (60.0-71.0) Female, N (%) 3,426 (38.5) 3,375 (37.9) Ethnicity, N (%) Caucasian 6,358 (71.4) 6,325 (71.1) Black 1,100 (12.4) 1,124 (12.6) Hispanic 1,121 (12.6) 1,140 (12.8) Blood pressure, mm (IQR) Systolic 134 (124-145) 134 (124-145) Diastolic 80 (75-87) 80 (75-87) Smoker, N (%) 1,400 (15.7) 1,420 (16.0) Family History, N (%) 997 (11.2) 1,048 (11.8) Metabolic Syndrome, N (%) 3,652 (41.0) 3,723 (41.8) Aspirin Use, N (%) 1,481 (16.6) 1,477 (16.6) All values are median (interquartile range) or N (%)
JUPITER Baseline Blood Levels (median, interquartile range) Ridker et al NEJM 2008 Rosuvastatin Placebo (N = 8901) (n = 8901) hscrp, mg/l 4.2 (2.8-7.1) 4.3 (2.8-7.2) LDL, mg/dl 108 (94-119) 108 (94-119) mmol/l 2.8 (2.43-3.08) 2.8 (2.43-3.08 HDL, mg/dl 49 (40 60) 49 (40 60) mmol/l 1.27 (1.03-1.55) 1.27 (1.03-1.55) Triglycerides, mg/l 118 (85-169) 118 (86-169) mmol/l 1.33 (0.96-1.91) 1.33 (0.97-1.91) Total Cholesterol, mg/dl 186 (168-200) 185 (169-199) mmol/l 4.82 (4.35-5.18) 4.79 (4.38-5.15) Glucose, mg/dl 94 (87 102) 94 (88 102) mmol/l 5.22 (4.83-5.66) 5.22 (4.88-5.66) HbA1c, % 5.7 (5.4 5.9) 5.7 (5.5 5.9) All values are median (interquartile range) [ Mean LDL = 104 mg/dl (2.69 mmol/l)]
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence NEJM 2008;359:2195-2207 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 0 1 2 3 4 Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER Primary Endpoint Understudied or Low Risk Subgroups NEJM 2008;359:2195-2207 Understudied Subgroups Women Age > 70 Black, Hispanic, Other Low Risk Subgroups Framingham Risk < 10 % BMI < 25 mg/m2 No Hypertension N HR (95%CI) 6,801 0.54 (0.37-0.80) 5,695 0.61 (0.46-0.82) 5,117 0.63 (0.41-0.98) 8,882 0.56 (0.38-0.83) 4,073 0.59 (0.40-0.87) 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 Event Reduction at All Levels of Baseline LDLC < 130 mg/dl Baseline Levels N LDLC <100 mg/dl 6,269 LDLC <90 mg/dl 3,687 LDLC <80 mg/dl 2,033 LDLC <70 mg/dl 1,022 LDLC <60 mg/dl 511 All Participants 17,802 0.20 0.5 1.0 2.0 4.0 Rosuvastatin Better Rosuvastatin Worse
JUPITER Absolute Risk Reduction Increases With Increasing Levels of hscrp Baseline hscrp N >10 _ mg/l 2,503 >9 _ mg/l >8 _ mg/l >7 _ mg/l >6 _ mg/l >5 _ mg/l >4 _ mg/l >3 _ mg/l >2 _ mg/l 3,071 3,839 4,723 5,897 7,425 9,726 12,939 17,802 0.20 0.5 1.0 2.0 Better Worse 1.0 2.0 3.0 4.0 5.0 Placebo Event Rate CR-16
JUPITER Dual Target Analysis: LDLC<70 mg/dl, hscrp<2 mg/l Cumulative Incidence 0.00 0.02 0.04 0.06 0.08 0 1 2 3 4 Placebo HR 1.0 (referent) LDL > 70 mg/dl and / or hscrp > 2 mg/l HR 0.64 (0.49-0.84) LDL < 70 mg/dl and hscrp < 2 mg/l HR 0.35 (0.23-0.54) Number at Risk Rosuvastatin Placebo Follow-up (years) 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168 P < 0.0001
JUPITER Total Venous Thromboembolism Cumulative Incidence 0.000 0.005 0.010 0.015 0.020 0.025 HR 0.57, 95%CI 0.37-0.86 P= 0.007 0 1 2 3 4 Placebo 60 / 8901-43 % Rosuvastatin 34 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182
JUPITER Venous Thromboembolism Unprovoked vs Provoked Cumulative Incidence 0.000 0.005 0.010 0.015 0.020 Cumulative Incidence Unprovoked Venous Thromboembolism Provoked Venous Thromboembolism 0.000 0.005 0.010 0.015 0.020 HR 0.61, 95% CI 0.35-1.09 P= 0.09 0 1 2 3 4 Follow-up (years) Placebo Rosuvastatin HR 0.52, 95% CI 0.28-0.97 P= 0.03 0 1 2 3 4 Follow-up (years) Placebo Rosuvastatin Clear clinical benefit in the absence of any bleeding hazard (hemmorrhagic events : rosuvastatin 258, placebo 275, P=0.45)
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
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 CR-22
JUPITER Achieved LDLC, Achieved hscrp, or Both? LDL (mg/dl) hscrp (mg/l) 140 120 100 80 60 40 20 0 5 4 3 LDL decrease 50 percent at 12 months Is the large benefit observed in the JUPITER trial due to lipid lowering, to inflammation inhibition, or to a combination of these two processes? 2 1 0 hscrp decrease 37 percent at 12 months 0 12 24 36 48 Months
JUPITER: Future RCT s on top of statin therapy with MTX, IL1B agonists, Romiflulast and other anti inflammatory agents will determine whether we were right or wrong