Presentation on theme: "“An Examination of the JUPITER Trial”"— Presentation transcript:
1 “An Examination of the JUPITER Trial” ModeratorKevin Winfield, MDMedical DirectorClear Lake Lipid CenterHouston, TX
2 DisclosureDisclosure of Unlabeled Use and Investigational Product Discussions:Dr. Winfield has indicated that his presentation will not include the discussion of unlabeled uses of commercial products or products that have not yet been approved by the FDA for use in the United States for any purpose.Disclosure of Affiliations and Significant Relationships:Dr. Winfield has received honoraria related to speakers’ bureau activities from Novartis, AstraZeneca, and Abbott Laboratories.
3 “An Examination of the JUPITER Trial” Paul Ridker, MDDirectorCenter for CardiovascularDisease PreventionDivision of Preventive MedicineBrigham and Women’s HospitalBoston, MA
4 Disclosure Disclosure of Affiliations and Significant Relationships: Dr. Ridker has received honoraria related to consulting activities from Schering-Plough, Sanofi-Aventis, AstraZeneca, Isis, Dade, Merck & Co., Novartis, Vascular Biogenics.He has also received grant support from research activities from National Heart, Lung, and Blood Institute, National Cancer Institute, American Heart Association, Doris Duke Charitable Foundation, Leducq Foundation, Donald W. Reynolds Foundation, James and Polly Annenberg La Vea Charitable Trusts, AstraZeneca, Novartis, Pharmacia, Roche, Sanofi-Aventis, Abbott Laboratories, Amgen.Equity: Co-inventor on patients held by Brigham and Women’s Hospital.
5 The JUPITER Trial JUPITER AHA November 9, 2008 A 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 AstraZeneca, 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 AstraZeneca.
6 hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated PHS 1997WHS 2000UK 2000MONICA 2004ARIC 2004Iceland 2004NHS 2004HPFUS 2004EPIC-N 2005Strong 2005Kuopio 2005FHS 2006CHS 2005PIMA 2005Fully Adjusted Relative Risk< 1 mg/L1 to 3 mg/L> 3 mg/L
7 What are the environmental and genetic influences on CRP? Relative Risk of Future CV Events“low risk”“moderate risk”“high risk”hsCRP (mg/L)Ridker et al Circulation 2004;109:
9 Clinical Relevance of Achieved LDL and Achieved hsCRP After Treatment with Statin TherapyCumulative Rate ofRecurrent Myocardial Infarction or Coronary Death (percent)0.100.10hsCRP>2 mg/LLDLC>70 mg/dL0.080.080.060.060.040.04hsCRP<2 mg/LLDLC<70 mg/dL0.020.020.000.000.00.51.01.52.02.50.00.51.01.52.02.5Follow-Up (years)Ridker et al NEJM 2005;352:20-28.
10 Clinical Relevance of Achieved LDL and Achieved hsCRP After Treatment with Statin Therapy0.00.51.01.52.02.50.000.020.040.060.080.10Recurrent Myocardial Infarction or Coronary Death(percent)Follow-Up (Years)LDL > 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/LLDL < 70 mg/dL, CRP > 2 mg/LLDL < 70 mg/dL, CRP < 2 mg/LRidker et al NEJM 2005;352:20-28.
11 JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? In 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 those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI ).*Ridker et al N Engl J Med 2001;344:
12 JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? AFCAPS/TexCAPS Low LDL SubgroupsLow LDL, Low hsCRPLow LDL, High hsCRPLow LDL, Low hsCRPLow LDL, High hsCRP[A][B]0.51.02.00.51.02.0RRStatin EffectiveStatin Not EffectiveStatin EffectiveStatin Not EffectiveHowever, 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 apost hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.Ridker et al, New Engl J Med 2001;344:
13 Justification for the Use of statins in Prevention: JUPITERPrimary ObjectivesRidker et al NEJM 2008Justification for the Use of statins in Prevention:an Intervention Trial Evaluating RosuvastatinTo investigate whether rosuvastatin 20 mg compared toplacebo would decrease the rate of first major cardiovascularevents among apparently healthy men and women withLDL < 130 mg/dL (3.36 mmol/L) who are nonethelessat increased vascular risk on the basis of an enhancedinflammatory response, as determined by hsCRP > 2 mg/L.To enroll large numbers of women and individuals of Black orHispanic ethnicity, groups for whom little data on primaryprevention with statin therapy exists.
14 JUPITERTrial DesignJUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRPMIStrokeUnstableAnginaCVD 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, VenezuelaRidker et al, Circulation 2003;108:
15 Baseline Clinical Characteristics JUPITERBaseline Clinical CharacteristicsRosuvastatin Placebo(N = 8901) (n = 8901)Age, years (IQR) ( ) ( )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 ( )Diastolic (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 (%)
23 Individual Components of the Primary Endpoint JUPITERIndividual Components of the Primary EndpointEndpoint Rosuvastatin Placebo HR 95%CI PPrimary Endpoint* <Non-fatal MI <Any MI <0.0002Non-fatal StrokeAny StrokeRevascularizationor Unstable Angina <MI, Stroke, CV Death <*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
24 Primary Endpoint – Subgroup Analysis I JUPITERPrimary Endpoint – Subgroup Analysis INP for InteractionMen11,0010.80Women6,801Age<658,5410.32Age > 659,261Smoker2,8200.63Non-Smoker14,975Caucasian12,6830.57Non-Caucasian5,117USA/Canada6,0410.51Rest of World11,761Hypertension10,2080.53No Hypertension7,586All Participants17,8020.250.51.02.04.0Rosuvastatin SuperiorRosuvastatin Inferior
25 Primary Endpoint – Subgroup Analysis II JUPITERPrimary Endpoint – Subgroup Analysis IINP for InteractionFamily HX of CHD2,0450.07No Family HX of CHD15,684BMI < 25 kg/m24,0730.70BMI kg/m7,0092BMI>30 kg/m26,675Metabolic Syndrome7,3750.14No Metabolic Syndrome10,296Framingham Risk<10%8,8820.99Framingham Risk > 10%8,895hsCRP > 2 mg/L Only6,375hsCRP > 2 mg/L Only6,375All Participants17,8020.250.51.02.04.0Rosuvastatin SuperiorRosuvastatin Inferior
26 Adverse Events and Measured Safety Parameters JUPITERAdverse Events and Measured Safety ParametersEvent 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 (0.1) (0.1) 0.44GFR (ml/min/1.73m2 at 12 mth) ( ) ( ) 0.02ALT > 3xULN (0.3) (0.2) 0.34Fasting glucose (24 mth) (91-107) (90-106) 0.12HbA1c (% at 24 mth) ( ) ( ) 0.01Glucosuria (12 mth) (0.5) (0.4) 0.64Incident Diabetes** (3.0) (2.4) 0.01*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)**Physician reported
27 Statins and the Development of Diabetes JUPITERStatins and the Development of DiabetesHR (95% CI)WOSCOPS Pravastatin(0.50–0.98)PROSPER Pravastatin(1.06–1.68)HPS Simvastatin(0.98–1.35)ASCOT-LLA Atorvastatin(0.91–1.44)PROVE-IT Atorvastatin VS Pravastatin(0.67–1.83)JUPITER Rosuvastatin(1.05–1.54)0.250.51.024Statin BetterStatin Worse
28 Secondary Endpoint – All Cause Mortality JUPITERSecondary Endpoint – All Cause MortalityHR 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
29 JUPITERConclusions – Efficacy IAmong 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.
30 JUPITERConclusions – Efficacy IIBenefits 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.
31 JUPITERConclusions - SafetyWith 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
32 Is the benefit observed in the JUPITER trial associated with achieving Achieved LDLC, Achieved hsCRP, or Both?Is the benefit observed in the JUPITERtrial associated with achievinga low level of LDLC,a low level of hsCRPor both?Do we need to achieve the “dual targets”of low LDLC and low hsCRP in order tomaximize the benefit of statin therapy?
33 JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM 2008Proportional reduction in vascular event rate (95% CI)CTTJUPITER PREDICTEDTNTPROVE-ITA-to-ZIDEALMean LDL cholesterol difference between treatment groups (mmol/l)
34 JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM 2008JUPITER OBSERVEDProportional reduction in vascular event rate (95% CI)CTTJUPITER PREDICTEDTNTPROVE-ITA-to-ZIDEALMean LDL cholesterol difference between treatment groups (mmol/l)
35 Following Initiation of Statin Therapy Clinical Importance of Achieving LDL-C < 70 mg/dL and hsCRP < 2 mg/LFollowing Initiation of Statin TherapyLDL>70, hsCRP>2LDL<70, hsCRP>2LDL>70, hsCRP<2LDL<70, hsCRP<2246810Recurrent Myocardial Infarction or Death(percent)180360540720900Follow-up (days)Follow-up (days)PROVE IT – TIMI 22NEJM 2005;352:20-28.A to ZCirculation 2006;114:281-8
36 1. LDL-C is a strong, independent predictor of future CV events PROVE IT, A to Z, AFCAPS/TexCAPS, REVERSAL Dose Correct Use of Statin Therapy Require Evaluation for both LDLC and hsCRP?1. LDL-C is a strong, independent predictor of future CV events2. Statins Lower LDL-C3. The level of LDL-C achieved after starting statin therapy predicts recurrent event rates (ie “lower is better”)1. hsCRP is a strong, independent predictor of future CV events2. Statins Lower hsCRP3. The level of hsCRP achieved after starting statin therapy predicts recurrent event rates (ie “lower is better”)Dual Goals for Statin Therapy :LDL-C < 70 mg/dL and hsCRP < 2 mg/L
37 Among men over 45 and post-menopausal women: JUPITERImplications for Primary PreventionRidker et al NEJM 2008A simple evidence based approach to statin therapyfor primary prevention.Among men over 45 and post-menopausal women:If diabetic or family history, treatIf LDLC > 160 mg/dL, treatIf hsCRP > 3 mg/L, treat
38 Public Health Implications JUPITERPublic Health ImplicationsRidker et al NEJM 2008Application of the simple screening and treatment strategytested in the JUPITER trial over a five-year period couldconservatively prevent more than 250,000 heart attacks,strokes, revascularization procedures, and cardiovasculardeaths in the United States alone.We thank the 17,802 patients and the >1,000 investigatorsworldwide for their personal time, effort, and commitmentto the JUPITER trial.
39 “An Examination of the JUPITER Trial” Christie Ballantyne, MDChief, Section of Atherosclerosis and Vascular MedicineDirector, Center for Cardiovascular Disease PreventionCo-Director, Lipid Metabolism and Atherosclerosis ClinicMethodist DeBakey Heart CenterBaylor College of MedicineHouston, TX
40 DisclosureDisclosure of Unlabeled Use and Investigational Product Discussions:Dr. Ballantyne has indicated that his presentation will not include the discussion of unlabeled uses of commercial products or products that have not yet been approved by the FDA for use in the United States for any purpose.Disclosure of Affiliations and Significant Relationships:Dr. Ballantyne has received honoraria related to speakers’ bureau activities from AstraZenece, Merck, Pfizer, Reliant, and Schering-Plough. He has also received grant support related to research activities from Abbott, ActivBiotics, Gene Logic, GlaxoSmithKline, Integrated Theraputics, Merck, Pfizer, Schering-Plough, Sanofi-Synthelabo, and Takeda. Dr. Ballantyne has also received honoraria related to consulting activities from Abbott, AstraZeneca, Atherogenics, Merck, Merck Schering-Plough, Novartis, Pfizer, Reliant, Schering-Plough, Sanfi-Synthelabo, Takeda, and GlaxoSmithKline.