JUPITER

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Ridker PM, et al. "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". The New England Journal of Medicine. 2008. 359(21):2195-2207.
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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 treatment to reduce ASCVD risk (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

  1. 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.
  2. Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.
  3. 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.