Presentation on theme: "The JUPITER Trial JUPITER AHA November 9, 2008"— Presentation transcript:
1 The JUPITER Trial JUPITER AHA November 9, 2008 Ridker - 162A Randomized Trial of Rosuvastatin in the Preventionof Cardiovascular Events Among 17,802 Apparently HealthyMen and Women With Elevated Levelsof C-Reactive Protein (hsCRP):The JUPITER TrialPaul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*,James Shepherd*, James Willerson, and Robert Glynn*on behalf of the JUPITER Trial Study GroupAn Investigator Initiated Trial Funded by Astra Zeneca, USA* These authors have received research grant support and/or consultation fees from one or morestatin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by theBrigham and Women’s Hospital that relate to the use of inflammatory biomarkers incardiovascular disease that have been licensed to Dade-Behring and Astra-Zeneca.
2 Background and Prior Work JUPITERBackground and Prior WorkRidker - 162Current guidelines for the prevention of myocardial infarctionstroke, and cardiovascular death endorse statin therapyamong patients with established vascular disease, diabetes,and among those with hyperlidemia.However, these screening and treatment strategies areinsufficient as half of all heart attack and stroke events occuramong apparently healthy men and women with average oreven low levels of cholesterol.To improve detection of individuals at increased risk forcardiovascular disease, physicians often measure highsensitivity C-reactive protein (hsCRP), an inflammatorybiomarker that reproducibly and independently predictsfuture vascular events and improves global riskclassification, even when cholesterol levels are low.
3 JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? Ridker - 162In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI ). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit.In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among study participants with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI ).However, while intriguing and of potential public health importance for the prevention of heart disease, 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.*Ridker et al N Engl J Med 2001;344:
4 JUPITERTrial DesignRidker - 162JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP17,802 participants from 216 countriesMIStrokeUnstableAnginaCVD DeathCABG/PTCARosuvastatin 20 mg (N=8901)No Prior CVD or DMMen >50, Women >60LDL <130 mg/dLhsCRP >2 mg/LPlacebo (N=8901)4-week run-inArgentina, 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
8 Adverse Events and Measured Safety Parameters JUPITERAdverse Events and Measured Safety ParametersRidker - 162Event Rosuvastatin Placebo PAny SAE 1,352 (15.2) 1,337 (15.5) 0.60Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34Myopathy (0.1) (0.1) 0.82Rhabdomyolysis (0.01)* (0.0) --Incident Cancer (3.4) (3.5) 0.51Cancer Deaths (0.4) (0.7) 0.02Hemorrhagic stroke (0.07) (0.10) 0.44GFR (ml/min/1.73m2 at 12 mth) ( ) ( ) 0.02ALT > 3xULN (0.26) (0.19) 0.34Fasting glucose (24 mth) (91-107) (90-106) 0.12HbA1c (% at 24 mth) ( ) ( ) 0.01Glucosuria (12 mth) (0.46) (0.41) 0.64Incident Diabetes** (2.8) (2.2) 0.02*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)**Physician reported
9 Secondary Endpoint – All Cause Mortality JUPITERSecondary Endpoint – All Cause MortalityRidker - 162HR 0.80, 95%CIP= 0.02Placebo 247 / 89010.06- 20 %0.050.04Cumulative Incidence0.03Rosuvastatin 198 / 89010.020.010.001234Follow-up (years)Number at RiskRosuvastatin8,9018,8478,7876,9994,3122,2681,6021,192683227Placebo8,9018,8528,7756,9874,3192,2951,6141,196684246
10 Conclusions – Efficacy I JUPITERConclusions – Efficacy IRidker - 162Among apparently healthy men and women with elevatedhsCRP but low LDL, rosuvastatin reduced by 47 percentincident myocardial infarction, stroke, and cardiovasculardeath.Despite evaluating a population with lipid levels widelyconsidered to be “optimal” in almost all current preventionalgorithms, the relative benefit observed in JUPITER wasgreater than in almost all prior statin trials.In this trial of low LDL/high hsCRP individuals who do notcurrently qualify for statin therapy, rosuvastatin significantlyreduced all-cause mortality by 20 percent.
11 Conclusions – Efficacy II JUPITERConclusions – Efficacy IIRidker - 162Benefits of rosuvastatin were consistent in all sub-groupsevaluated regardless of age, sex, ethnicity, or other baselineclinical characteristic, including those with elevated hsCRPand no other major risk factor.Rates of hospitalization and revascularization were reducedby 47 percent within a two-year period suggesting that thescreening and treatment strategy tested in JUPITER islikely to be cost-effective, benefiting both patients and payers.The Number Needed to Treat in JUPITER was 25 for the primaryendpoint, a value if anything smaller than that associatedwith treating hyperlipidemia in primary prevention.
12 With regard to safety , the JUPITER results Conclusions - SafetyRidker - 162With regard to safety , the JUPITER resultsshow no increase in serious adverse events among thoseallocated to rosuvastatin 20 mg as compared to placeboin a setting where half of the treated patients achievedlevels of LDL< 55 mg/dL (and 25 percent had LDL < 44mg/dL).show no increase in myopathy, cancer, hepaticdisorders, renal disorders, or hemorrhagic stroke withtreatment duration of up to 5 yearsshow no increase in systematically monitored glucose orglucosuria during follow-up, but small increases inHbA1c and physician reported diabetes similar to thatseen in other major statin trials