JUPITER
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Clinical Question
In patients with normal LDL and elevated high-sensitivity CRP (HS-CRP), does rosuvastatin reduce the incidence of major CV events?
Bottom Line
Among patients with normal LDL but elevated HS-CRP, rosuvastatin reduces the incidence of CV events.
Major Points
Multiple trials (including HPS, WOSCOPS, TNT, LIPID, CARE, 4S, and PROVE IT-TIMI 22) have demonstrated the efficacy of statins in primary and secondary prevention of CV events among patients with hyperlipidemia or known CAD, respectively. However, the role of statins for patients with elevated inflammatory markers, which have been linked to occult CAD, had not been well studied until the JUPITER trial.
The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial randomized nearly 18,000 patients with normal lipids and elevated HS-CRP to either rosuvastatin or placebo, and followed patients to their first CV event. JUPITER demonstrated that rosuvastatin not only reduces LDL and HS-CRP levels, but also reduces the incidence of major CV events (HR 0.77 per 100 person-years). The authors estimate a NNT of 25; ie, treating 25 individuals with rosuvastatin will prevent one major CV event at 5 years. Patients treated with rosuvastatin were more likely to have a new diagnosis of DM after initiation of therapy. (A 2010 meta-analysis[1] estimated that 260 patients would need to be treated with statins for 4 years in order to cause one case of incident DM.)
JUPITER was criticized for being truncated early, and thus quite possibly overestimating the effect of treatment. There was also inadequate treatment in the placebo arm, based upon the low proportion of patients who received aspirin who had an intermediate risk of CAD by Framingham risk assessment, as well as the large minority of patients who had inadequately controlled hypertension. There were also concerns that the study did not include Asian participants, who metabolize rosuvastatin with different pharmacokinetics. In addition, there was no clear indication that an elevated HS-CRP was required for rosuvastatin to confer a benefit, since individuals with HS-CRP <2 mg/L were not evaluated.
Guidelines
ACC/AHA Cholesterol Guidelines (2013, adapted)[2]
- Statins for primary prevention in non-diabetics:
- No targets for specific LDL or HDL cholesterol levels
- If age ≥21 and LDL-C ≥190 mg/dL, start high-intensity therapy (class I, level B, NHLBI grade B)
- If not tolerating high-intensity therapy, use maximum tolerated dose
- In adults age 40-75 with LDL-C 70-189 mg/dL, use Pooled Cohort Equation to estimate 10 year ASCVD risk individuals (class I, level B, NHLBI grade E):
- If ASCVD risk ≥7.5%, start moderate or high intensity statin therapy (class I, level B, NHLBI grade A)
- If ASCVD risk 5 to <7.5%, it is reasonable to offer moderate intensity statin therapy (Class IIa, level B, NHLBI grade C)
Design
- Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- N=17,802 patients with normal LDL and elevated HS-CRP
- Rosuvastatin (n=8,901)
- Placebo (n=8,901)
- Setting: 1315 centers in 26 countries
- Enrollment: 2003-2006
- Median follow-up: 1.9 years
- Analysis: Intention-to-treat
- Primary outcome: Combined endpoint of first major CV event
Population
Inclusion Criteria
- Men >50 years, or women >60 years
- LDL <130 mg/dL
- HS-CRP >2.0 mg/L
- Triglycerides <500 mg/dL
- No history of CV disease
Exclusion Criteria
- Use of lipid-lowering medications ever in life
- Post-menopausal hormone replacement therapy use at time of inclusion
- ALT >2x ULN
- CK >3x ULN
- Cr >2.0 mg/dL
- Diabetes
- SBP >190 mmHg or DBP >100 mmHg
- Cancer (except basal or squamous cell carcinoma of the skin) in the prior 5 years
- TSH >1.5x ULN
- Recent alcohol or drug abuse
- Another medical condition that might compromise safety or successful completion of the study
- Inflammatory conditions (including, but not limited to, severe arthritis, lupus, IBD)
- Use of immunosuppressants (including, but not limited to, cyclosporine, tacrolimus, azathioprine, long-term oral glucocorticoids)
Baseline Characteristics
All ranges given are averages of the intervention and placebo groups.
- Age: 66 years
- Female: 37.9-38.5%
- Race and ethnic data:
- White: 71.1-71.4%
- Black: 12.4-12.6%
- Hispanic: 12.6-12.8%
- Other/unknown: 3.5-3.6%
- BMI: 28.3-28.4%
- SBP: 134 mmHg
- DBP: 80 mmHg
- Smoker: 15.7-16.0%
- Family history of premature CAD: 11.2-11.8%
- Metabolic syndrome: 41.0-41.8%
- Aspirin use: 16.6%
- Labs:
- HS-CRP: 4.2-4.3 mg/L
- LDL: 108 mg/dL
- HDL: 49 mg/dL
- Triglycerides: 118 mg/dL
- Total cholesterol: 185-186 mg/dL
- Glucose: 94 mg/dL
- Hgb A1C: 5.7%
- GFR 73.3-73.6 mL/min/1.73 m2
Interventions
- Four-week placebo-only run-in phase; those who took more than 80% of their tablets were enrolled in the trial
- Randomized to rosuvastatin 20mg daily or placebo
- Follow-up visits were scheduled at 13 weeks then every 6 months after randomization until month 60
- Individual sites performed telephone follow-ups with patients in between the follow-up visits
- Patients followed up in a close-out visit following cessation of the study
Outcomes
Comparisons are rosuvastatin vs. placebo. Rates given as events per 100 person-years.
Primary Outcome
- First major CV event (non-fatal MI, non-fatal stroke, hospitalization for UA, arterial revascularization procedure, or death from CV causes)
- 0.77 vs. 1.36 (HR 0.56; 95% CI 0.46-0.69)
Secondary Outcomes
- Non-fatal MI
- 0.12 vs. 0.33 (HR 0.35; 95% CI 0.22-0.58)
- Any MI
- 0.17 vs. 0.37 (HR 0.46; 95% CI 0.30-0.70)
- Non-fatal stroke
- 0.16 vs. 0.31 (HR 0.52; 95% CI 0.33-0.80)
- Hospitalization for UA
- 0.09 vs. 0.14 (HR 0.59; 95% CI 0.32-1.10; P=NS)
- Arterial revascularization procedure
- 0.38 vs. 0.71 (HR 0.54; 95% CI 0.41-0.72)
- Arterial revascularization procedure or hospitalization for UA
- 0.41 vs. 0.77 (HR 0.53; 95% CI 0.40-0.70)
- MI, stroke, or confirmed death from CV causes
- 0.45 vs. 0.85 (HR 0.53; 95% CI 0.40-0.69)
- CV mortality
- Not reported
- All-cause mortality
- Known date: 0.96 vs. 1.19 (HR 0.81; 95% CI 0.67-0.98)
- Any death on any date: 1 vs. 1.25 (HR 0.80; 95% CI 0.67-0.97)
Subgroup Analysis
- Primary endpoint
- No significant differences between any of the subgroups including women, men, age, race/ethnic groups, region, status of traditional risk factors, or Framingham risk score above or below 10%
Additional Analyses
P<0.001 except where otherwise stated
- HS-CRP in mg/L
- 12 months: 2.2 vs. 3.5
- 24 months: 2.2 vs. 3.5
- 36 months: 2.0 vs. 3.5
- 48 months: 1.8 vs. 3.3
- LDL in mg/dL
- 12 months: 55 vs. 110
- 24 months: 54 vs. 108
- 36 months: 53 vs. 106
- 48 months: 55 vs. 109
- HDL in mg/dL
- 12 months: 52 vs. 50
- 24 months: 52 vs. 50
- 36 months: 50 vs. 49 (P=0.003)
- 48 months: 50 vs. 50 (P=0.34)
- Triglycerides in mg/dL
- 12 months: 99 vs. 119
- 24 months: 99 vs. 116
- 36 months: 106 vs. 123
- 48 months: 99 vs. 118
Adverse Events
- Serious adverse events
- 1352 vs. 1377 events (P=0.60)
- Myopathy
- 10 vs. 9 events (P=0.82)
- Rhabdomyolysis
- One non-fatal case in the rosuvastatin group (the authors note that it was associated with "febrile influenza, pneumonia, and trauma-induced myopathy" in a 90 year old female)
- Muscle weakness
- No significant difference
- New cancer
- No significant difference
- Death from cancer
- 0.4% vs. 0.7% (P=0.02)
- Hematologic, GI, hepatic, or renal disorders
- No significant difference
- Elevation of alanine aminotransferase above 3x the upper limit of normal
- Similar between the two groups
- GFR
- 66.8 vs. 66.6 mL/min/1.73 m2 (P=0.02)
- Fasting blood glucose or glucosuria
- No significant difference
- A1C level
- 5.9% vs. 5.8% (P=0.001)
- Newly-diagnosed diabetes
- 270 vs. 216 reports (P=0.01)
- Intracranial hemorrhage
- No difference
Criticisms
- Many patients were not on optimal medical therapy for their risk factors (eg, aspirin therapy if high Framingham score)[3]
- Early truncation of the trial resulted in only a 2 year follow up, and likely overestimation of treatment effect[3]
- Did not include Asian participants, important because this group has distinct rosuvastatin pharmacokinetics[3]
- Individuals with normal HS-CRP values (eg, <2 g/L) were not studied
- Did not adequately address increased risk of new-onset DM[3]
Funding
Sponsored by Astra Zeneca who collected the trial data and monitored study sites. Authors with multiple financial conflicts disclosed, including the primary author who owns the patent for the HS-CRP assay.
Further Reading
- ↑ Sattar N, et al. "Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials." The Lancet. 2010;375(9716):735-742.
- ↑ Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014. 63:2889-934.
- ↑ 3.0 3.1 3.2 3.3 Multiple authors. "Correspondence: Rosuvastatin in patient with elevated C-reactive protein. The New England Journal of Medicine. 2009;360:1038-1042.