The JUPITER trial: What does it tell us? Alice Y.Y. Cheng, MD, FRCPC January 24, 2009
Learning Objectives 1. Understand the role of statin therapy in the primary and secondary prevention of stroke 2. Explain the rationale and major findings of the JUPITER trial 3. Understand the practical applicability of the JUPITER trial and role of hs-crp testing in clinical practice
Statins Lower LDL-C C = Lower CAD Risk 4S-Pl 25 Rx - Drug group Pl - Placebo group Percent with CHD event 20 15 10 5 4S-Rx LIPID-Pl CARE-Pl HPS-Pl CARE-Rx LIPID-Rx HPS-Rx TNT-A10 TNT-A80 0 End of study LDL-C 1.3 1.8 2.3 2.84 3.36 3.87 4.39 4.91 5.43 mmol/l Adapted from Kastelein JJ. Atherosclerosis 1999;143(Suppl 1):S17 S21. Heart Protection Study Collaborative Group. Lancet 2002;360:7 22
TNT: Stroke (Fatal or Nonfatal) Proportion of patients experiencing fatal or nonfatal stroke 0.04 0.03 0.02 0.01 HR = 0.75 (95%CI 0.59, 0.96) P=0.02 Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction = 25% 0 0 1 2 3 4 5 6 Time (years) LaRosa JC, et al. N Eng J Med. 2005;352
Heart Protection Study (HPS): Major Vascular Events VASCULAR EVENT SIMVASTATIN PLACEBO EVENT RATE RATIO (95% CI) (n = 10,269) (n = 10,267) Major coronary 8.7% 11.8% 27% RRR* (21-33%) Any stroke 4.3% 5.7% 25% RRR* (15-34%) Any revascularizations 9.1% 11.7% 24% RRR* (17-30%) ANY OF ABOVE 19.8% 25.2% 24% RRR* (19-28%) *p < 0.0001 0.4 0.6 0.8 1.0 1.2 1.4 STATIN better PLACEBO better Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Fatal or Non-fatal Stroke 16% Placebo Atorvastatin 16% RRR Fatal or Non-fatal Stroke (%) 12% 8% 4% NNT=46 Adjusted HR (95% CI)=0.84 (0.71, 0.99), p=0.03 0% 0 1 2 3 4 5 6 Years Since Randomization Despite the significant risk reduction in the primary endpoint with atorvastatin 80 mg, there was a small but significant increase in hemorrhagic stroke with atorvastatin 80 mg vs. placebo (0.9% absolute risk reduction, p-value 0.02) The SPARCL Investigators. N Engl J Med. 2006 Aug 10;355(6):549-59.
Prevalence of conventional risk factors in male patients with CHD Three 8.9% Four (0.9%) 19.4% None Two 27.8% 43.0% One Total male patients=87 869 CHD=coronary heart disease smoking, hypertension, hypercholesterolaemia and diabetes mellitus Khot UN et al. JAMA 2003; 290: 898 904
AFCAPS/TexCAPS TexCAPS: baseline LDL-C C and hscrp Study group Rate of cardiovascular events NNT Lovastatin Placebo Low LDL-C/low hscrp 0.025 0.022 N/A Low LDL-C/high hscrp 0.029 0.051 48 High LDL-C/low hscrp 0.020 0.050 33 High LDL-C/high hscrp 0.038 0.055 58 Median LDL-C=3.9 mmol/l (149 mg/dl). Median hscrp=1.6 mg/l AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hscrp=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event Ridker PM et al. N Engl J Med 2001; 344: 1959 1965
Incidence of Recurrent MI or CHD Death according to Achieved Levels of Both LDL-C C and CRP: PROVE IT TIMI TIMI 22 Recurrent MI or Coronary Death (%) 0.10 0.08 0.06 0.04 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Follow-up (Years) Ridker PM et al. N Engl J Med 2005;352:20-28. 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 Slide Source LipidsOnline www.lipidsonline.org
Objective Low LDL-C (<3.36 mmol/l, TG <5.65 mmol/l) Elevated CRP levels (CRP levels 2.0 mg/l) Men aged 50 years; women aged 60 years Does long-term treatment with rosuvastatin 20 mg daily decrease the rate of first major cardiovascular events compared with placebo? Ridker PM. Circulation 2003; 108: 2292 2297. Ridker PM. Am J Cardiol 2007; 100: 1659 1664.
JUPITER - Patient Flow 89,890 subjects screened 17,802 randomised Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Lost to follow up n=37 Completed study n=8,857 Completed study n=8,864 Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER study design N=17,802 Placebo run-in Rosuvastatin 20 mg (n~8901) Placebo (n~8901) Visit: Week: 1 6 2 4 3 0 4 13 6-month intervals Final 3 4 y Lead-in/ eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c =glycated haemoglobin Ridker PM. Circulation 2003; 108: 2292 2297. Ridker PM. Am J Cardiol 2007; 100: 1659 1664.
JUPITER study endpoints Primary first occurrence of a major CV event (CV death, stroke, MI, unstable angina or arterial revascularisation) Secondary Efficacy (incident diabetes mellitus, venous thromboembolic events, bone fractures) Safety (total mortality non-cv mortality, adverse events)
Baseline characteristics Male, % Mean age, years Race, % White Mean BMI, kg/m 2 Mean blood pressure, mmhg Systolic/diastolic Current smoker, % Metabolic syndrome Randomised (n=17,802) 61.8 66.3 71.3 28.4 134/80 15.8 41% BMI=body mass index Ridker PM et al. Am J Cardiol 2007; 100: 1659 1664.
Laboratory parameters at baseline Total cholesterol LDL-C HDL-C Non-HDL-C Triglycerides Glucose hscrp (mg/l) HbA 1c (%) mmol/l 4.79 2.79 1.27 3.47 1.33 5.2 4.3 5.7 Values expressed as median (interquartile range). For hscrp, values are the mean of the screening & randomisation visits. LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; hscrp=median high sensitivity C- reactive protein; HbA 1c =glycosylated haemoglobin Ridker PM et al. Am J Cardiol 2007; 100: 1659 1664.
JUPITER - Primary Endpoint Percent of patients with primary endpoint 9 8 7 6 5 4 3 2 1 0 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 0 1 2 3 4 5 Years Number at risk Rosuvastatin 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 Rosuvastatin 20 mg NNT for 2 yrs = 95 5 yrs* = 25 Ridker P et al. N Eng J Med 2008;359: 2195-2207
Tolerability and Safety Placebo Rosuvastatin P value [n=8901] [n=8901] Adverse Events, (%) Any serious adverse event 15.5 15.2 0.60 Muscle weakness, stiffness, pain 15.4 16.0 0.34 Myopathy 0.1 0.1 0.82 Rhabdomyolysis 0.0 <0.1 * ---- Newly diagnosed cancer 3.5 3.4 0.51 Death from cancer 0.7 0.4 0.02 Gastrointestinal disorders 19.2 19.7 0.43 Renal disorders 5.4 6.0 0.08 Bleeding 3.1 2.9 0.45 Hepatic disorders 2.1 2.4 0.13 Other events, (%) Newly diagnosed diabetes ** 2.4 3.0 0.01 Haemorrhagic stroke 0.1 0.1 0.44 *Occurred after trial completion; **physician -reported Ridker P et al. N Eng J Med 2008;359: 2195-2207
Interpretation 44% RRR in primary endpoint, 20% RRR mortality in PRIMARY PREVENTION 1.9 years of median follow-up Absolute risk reduction is low because absolute risk was low Treatment well tolerated Hs-CRP to FURTHER RISK STRATIFY Magnitude of LDL red n = magnitude of benefit
Interpretation If someone you would already treat do NOT check hs-crp If someone you would not typically treat consider hs-crp to further risk stratify If hs-crp > 2 mg/l consider treat Consider false positives Go big or go home
Summary Ischemic stroke / TIA = high vascular risk Start statin therapy LDL < 2.0 AND >50% red n JUPITER identified previously unrecognized group at higher risk Hs-CRP only in those you re not sure if treat (intermediate risk, male > 50, female > 60) Go big or go home