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“An Examination of the JUPITER Trial”

“An Examination of the JUPITER Trial”. Moderator Kevin Winfield, MD Medical Director Clear Lake Lipid Center Houston, TX. Disclosure. Disclosure of Unlabeled Use and Investigational Product Discussions:

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“An Examination of the JUPITER Trial”

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  1. “An Examination of the JUPITER Trial” Moderator Kevin Winfield, MD Medical Director Clear Lake Lipid Center Houston, TX

  2. Disclosure • Disclosure 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, MD Director Center for Cardiovascular Disease Prevention Division of Preventive Medicine Brigham and Women’s Hospital Boston, 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. JUPITER AHA November 9, 2008 A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17,802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hsCRP): The JUPITER Trial Paul 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 Group An Investigator Initiated Trial Funded by AstraZeneca, USA * These authors have received research grant support and/or consultation fees from one or more statin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.

  6. NHS 2004 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland 2004 PHS 1997 Fully Adjusted Relative Risk HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 PIMA 2005 FHS 2006 CHS 2005 hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated < 1 mg/L 1 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;109:1955-59

  8. Inflammation, Statin Therapy, and hsCRP: Initial Observations P Trend = 0.005 -21.6% (P=0.004) 3 0.25 0.24 Placebo 2 0.23 0.22 Relative Risk Median hs-CRP (mg/dL) 0.21 1 Pravastatin 0.20 0.19 0 0.18 Pravastatin Placebo Pravastatin Placebo 5 Years Baseline Inflammation Absent Inflammation Present Circulation. 1999;100:230-235. Circulation. 1998;98:839–844.

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

  10. Clinical Relevance of Achieved LDL and Achieved hsCRP After Treatment with Statin Therapy 0.10 0.10 0.08 0.08 0.06 0.06 Recurrent Myocardial Infarction or Coronary Death (percent) 0.04 0.04 0.02 0.02 0.00 0.0 0.0 0.0 0.0 0.5 0.5 0.5 0.5 1.0 1.0 1.0 1.0 1.5 1.5 1.5 1.5 2.0 2.0 2.0 2.0 2.5 2.5 2.5 2.5 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 Ridker 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 0.56-2.08). 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 0.34-0.98). *Ridker et al N Engl J Med 2001;344:1959-65

  12. 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 2.0 1.0 0.5 2.0 1.0 RR Statin Effective Statin Not Effective Statin Effective Statin Not Effective However, 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. Ridker et al, New Engl J Med 2001;344:1959-65

  13. JUPITER Primary Objectives Ridker et al NEJM 2008 Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 2 mg/L. To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists.

  14. JUPITER Trial Design JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular EventsAmong 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 Ridker et al, Circulation 2003;108:2292-2297.

  15. 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 (%)

  16. JUPITER Baseline Blood Levels (median, interquartile range) 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) HDL, mg/dL 49 (40 – 60) 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199) Glucose, mg/dL 94 (87 – 102) 94 (88 – 102) HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dL ]

  17. 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) 108 192 150 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

  18. JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP LDL (mg/dL) HDL (mg/dL) LDL decrease 50 percent at 12 months HDL increase 4 percent at 12 months hsCRP (mg/L) TG (mg/dL) hsCRP decrease 37 percent at 12 months TG decrease 17 percent at 12 months 0 12 24 36 48 Months Months

  19. JUPITER Primary Trial Endpoint :MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 0.08 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 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

  20. JUPITER Primary Trial Endpoint :MI, Stroke, UA/Revascularization, CV Death 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 0 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

  21. JUPITER Myocardial Infarction, Stroke, Cardiovascular Death HR 0.53, 95%CI 0.40-0.69 P < 0.00001 0.05 Placebo (N = 157) 0.04 - 47 % 0.03 Cumulative Incidence 0.02 Rosuvastatin (N = 83) 0.01 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,643 8,437 6,571 3,921 1,979 1,370 998 551 159 Placebo 8,901 8,633 8,381 6,542 3,918 1,992 1,365 979 550 181

  22. JUPITER Arterial Revascularization / Unstable Angina 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 0 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

  23. JUPITER Individual Components of the Primary Endpoint Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001 Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001 Any MI 31 68 0.46 0.30-0.70 <0.0002 Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003 Any Stroke 33 64 0.52 0.34-0.79 0.002 Revascularization or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001 MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001 *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

  24. JUPITER Primary Endpoint – Subgroup Analysis I N P for Interaction Men 11,001 0.80 Women 6,801 Age < 65 8,541 0.32 Age > 65 9,261 Smoker 2,820 0.63 Non-Smoker 14,975 Caucasian 12,683 0.57 Non-Caucasian 5,117 USA/Canada 6,041 0.51 Rest of World 11,761 Hypertension 10,208 0.53 No Hypertension 7,586 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior

  25. JUPITER Primary Endpoint – Subgroup Analysis II N P for Interaction Family HX of CHD 2,045 0.07 No Family HX of CHD 15,684 2 4,073 0.70 BMI < 25 kg/m 7,009 BMI 25-29.9 kg/m 2 6,675 BMI > 30 kg/m 2 Metabolic Syndrome 7,375 0.14 No Metabolic Syndrome 10,296 Framingham Risk < 10% 8,882 0.99 Framingham Risk > 10% 8,895 hsCRP > 2 mg/L Only 6,375 hsCRP > 2 mg/L Only 6,375 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior

  26. JUPITER Adverse Events and Measured Safety Parameters Event Rosuvastatin Placebo P Any SAE 1,352 (15.2) 1,337 (15.5) 0.60 Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34 Myopathy 10 (0.1) 9 (0.1) 0.82 Rhabdomyolysis 1 (0.01)* 0 (0.0) -- Incident Cancer 298 (3.4) 314 (3.5) 0.51 Cancer Deaths 35 (0.4) 58 (0.7) 0.02 Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44 GFR (ml/min/1.73m2 at 12 mth)66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02 ALT > 3xULN 23 (0.3) 17 (0.2) 0.34 Fasting glucose (24 mth)98 (91-107) 98 (90-106) 0.12 HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01 Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64 Incident Diabetes** 270 (3.0) 216 (2.4) 0.01 *Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%) **Physician reported

  27. JUPITER Statins and the Development of Diabetes 0.25 0.5 1.0 2 4 HR (95% CI) WOSCOPS Pravastatin 0.70 (0.50–0.98) 1.34 (1.06–1.68) PROSPER Pravastatin 1.20 (0.98–1.35) HPS Simvastatin 1.20 (0.91–1.44) ASCOT-LLA Atorvastatin PROVE-IT Atorvastatin VS Pravastatin 1.11 (0.67–1.83) JUPITER Rosuvastatin 1.25 (1.05–1.54) Statin Better Statin Worse

  28. JUPITER Secondary Endpoint – All Cause Mortality 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 0 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

  29. JUPITER Conclusions – Efficacy I Among apparently healthy men and women with elevated hsCRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death. Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials. In this trial of low LDL/high hsCRP individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced all-cause mortality by 20 percent.

  30. JUPITER Conclusions – Efficacy II Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP and no other major risk factor. Rates of hospitalization and revascularization were reduced by 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers. The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention.

  31. JUPITER Conclusions - Safety With regard to safety , the JUPITER results show no increase in serious adverse events among those allocated to rosuvastatin 20 mg as compared to placebo in a setting where half of the treated patients achieved levels of LDL< 55 mg/dL (and 25 percent had LDL < 44 mg/dL). show no increase in myopathy, cancer, hepatic disorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years show no increase in systematically monitored glucose or glucosuria during follow-up, but small increases in HbA1c and physician reported diabetes similar to that seen in other major statin trials

  32. JUPITER Achieved LDLC, Achieved hsCRP, or Both? Is the benefit observed in the JUPITER trial associated with achieving a low level of LDLC, a low level of hsCRP or both? Do we need to achieve the “dual targets” of low LDLC and low hsCRP in order to maximize the benefit of statin therapy?

  33. JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM 2008 Proportional reduction in vascular event rate (95% CI) CTT JUPITER PREDICTED TNT PROVE-IT A-to-Z IDEAL Mean LDL cholesterol differencebetween treatment groups (mmol/l)

  34. JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM 2008 JUPITER OBSERVED Proportional reduction in vascular event rate (95% CI) CTT JUPITER PREDICTED TNT PROVE-IT A-to-Z IDEAL Mean LDL cholesterol differencebetween treatment groups (mmol/l)

  35. 10 8 8 6 6 4 4 2 2 0 Clinical Importance of Achieving LDL-C < 70 mg/dL and hsCRP < 2 mg/L Following Initiation of Statin Therapy LDL>70, hsCRP<2 LDL<70, hsCRP>2 LDL>70, hsCRP>2 LDL<70, hsCRP<2 Recurrent Myocardial Infarction or Death (percent) 0 540 720 900 180 360 Follow-up (days) Follow-up (days) A to Z Circulation 2006;114:281-8 PROVE IT – TIMI 22 NEJM 2005;352:20-28.

  36. PROVE IT, A to Z, AFCAPS/TexCAPS, REVERSALDose Correct Use of Statin Therapy Require Evaluation for both LDLC and hsCRP? • 1. hsCRP is a strong, independent predictor of future CV events • 2. Statins Lower hsCRP • 3. The level of hsCRP achieved after starting statin therapy predicts recurrent event rates (ie “lower is better”) • 1. LDL-C is a strong, independent predictor of future CV events • 2. Statins Lower LDL-C • 3. The level of LDL-C 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. JUPITER Implications for Primary Prevention Ridker et al NEJM 2008 A simple evidence based approach to statin therapy for primary prevention. Among men over 45 and post-menopausal women: If diabetic or family history, treat If LDLC > 160 mg/dL, treat If hsCRP > 3 mg/L, treat

  38. JUPITER Public Health Implications Ridker et al NEJM 2008 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. We thank the 17,802 patients and the >1,000 investigators worldwide for their personal time, effort, and commitment to the JUPITER trial. www.brighamandwomens.org/jupitertrial

  39. “An Examination of the JUPITER Trial” Christie Ballantyne, MD Chief, Section of Atherosclerosis and Vascular Medicine Director, Center for Cardiovascular Disease Prevention Co-Director, Lipid Metabolism and Atherosclerosis Clinic Methodist DeBakey Heart Center Baylor College of Medicine Houston, TX

  40. Disclosure • Disclosure 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.

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