IMPROVE-IT - Ezetimibe added to statin following ACS

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Visual abstract - Ezetimibe.png

Bottom line: In patients within 10 days of ACS, ezetimibe lowered LDL by 0.4 mmol/L and reduced the relative risk of CV events by 6% more than placebo when added to simvastatin. At a median 6 years, the addition of ezetimibe had no effect on mortality and reduced the absolute risk of any MI by 1.7% (NNT 59) and stroke by 0.6% (NNT 167).

 

Context

  • Ezetimibe reduces LDL by ~25%
  • Prior to IMPROVE-IT, none of the available ezetimibe trials enrolled enough patients to adequately evaluate cardiovascular outcomes

    Patients

    • Multicenter (1147 sites in 39 countries)
    • Inclusion:
      • Men & women 50+ y
      • Hospitalized for ACS within 10 days
      • LDL 1.3-3.2 mmol/L measured <24 hours of ACS onset (1.3-2.6 mmol/L if receiving lipid-lowering therapy at baseline)
    • Exclusion:
      • Clinically unstable (cardiogenic shock, severe decompensated HF, acute MR, acute VSD)
      • Recurrent symptoms of cardiac ischemia
      • Arrhythmias (vfib, sustained VT, 3o AVB, 2o AVB type 2) 
      • Planned CABG
      • CrCl <30 mL/min
      • Active liver disease
      • Statin dose equal to simvastatin >40 mg/d
    • ? screened -> 18,144 randomized
    • "Average" patient @ baseline
      • 64 y
      • Female 24%
      • White 84%, North American 38%
      • Index event: STEMI 29%, NSTEMI 47%, unstable angina 24%
      • PCI 70%
      • Time from event to randomization: 5 days
      • PMHx
        • Current smoker 33%
        • Previous MI 21%, PCI 20%, CABG 9%
        • HTN 61%
        • HF 4%
        • PAD 5%
        • Diabetes 27%
      • LDL: 2.4 mmol/L
      • Meds
        • ASA 97%
        • P2Y12 inhibitor 87%
        • ACEI 75%
        • Beta-blocker 87%

    Interventions & co-interventions

    • I: Ezetimibe 10 mg PO once daily (60% still taking at end of study)
    • C: Placebo
      • Co-interventions:
        • Simvastatin 40 mg PO once daily
          • Before 2011 amendment: If LDL >2.0 mmol/L x2 consecutive measurements: Simvastatin increased to 80 mg daily
        • If LDL >2.6 mmol/L x2 consecutive measurements: Study drug discontinued, started on open-label lipid-lowering therapy (outcomes followed & included in intention-to-treat analysis)

    Results @ median 6 years

    • LDL lowered by ~0.4 mmol/L (24%) more with ezetimibe than placebo
      • @ baseline: 2.4 mmol/L in both groups
      • @ 1 y: 1.4 vs 1.8 mmol/L
    • Statistically significant reduction in primary outcome (CV death, non-fatal MI, unstable angina requiring hospitalization, coronary revascularization occurring >30 days after randomization, or non-fatal stroke) with ezetimibe+simvastatin versus placebo+simvastatin: Hazard ratio (HR) 0.94 (95% confidence interval 0.89-0.99, p=0.016)
      • 32.7% vs 34.7% (NNT 50)
    • Key secondary outcomes
      • Death: 15.4% vs 15.3% (p=0.78)
      • Serious adverse events: Not reported
      • Any MI: 13.1% vs 14.8% (NNT 59, p=0.002)
      • Any stroke: 4.2% vs 4.8% (NNT 167, p=0.05)
    • No statistically significant differences in any adverse events
      • Cancer: 10.2% in both groups (p=0.57)
      • ALT/AST elevated 3x or more above ULN: 2.5% vs 2.3% (p=0.43)
      • Rhabdomyolysis, myopathy, or myalgias with CK elevation 5x or more above ULN: 0.6% in both groups (p=0.90)
    • Subgroups
      • Statistically significant (p<0.10) tests for interaction suggested greater relative risk reduction in primary outcome with OLDER patients (both >65 or >75), and in those with diabetes.

    Issues with internal validity?

    • Randomized, allocation-concealed, all-blind (investigators, clinicians, patients) trial analyzed using intent-to-treat analysis
    • Missing data for ~10% for primary outcome (sensitivity analyses did not show that this made any meaningful difference)
    • Notes:
      • Randomization stratified according to: Prior use of lipid-lowering therapy (yes/no), type of ACS, enrolment in EARLY ACS trial (yes/no)
      • Study continued until each patient followed >2.5 y + occurrence of 5250 events

    Additional publications of IMPROVE-IT

    • The TIMI Risk Score in Secondary Prevention may be useful to identify patients more likely to benefit from adding ezetimibe
      • 9-point risk score, 1 point for each:
        • Prior CVD: HF, prior CABG, prior stroke, PAD
        • CV risk factors: Age 75+ y, smoking, HTN, diabetes, eGFR <60
      • Significant interaction (p=0.01) between TIMI Risk Score for Secondary Prevention & benefit of adding ezetimibe in IMPROVE-IT:
        • Low risk (score 0-1): Simva+ezetimibe 14.0%, simva+placebo 13.1% (no benefit, non-significant 5% relative risk increase)
        • Intermediate risk (score 2): Simva+ezetimibe 19.3%, simva+placebo 21.5% (NNT 46, 11% relative risk reduction [RRR]; similar to overall IMPROVE-IT population)
        • High (score 3+): SImva+ezetimibe 33.9%, simva+placebo 40.2% (NNT 16, RRR 19%)
      • Importantly, baseline LDL not included in this risk score, & absolute LDL reduction was similar in all risk groups (i.e. ~0.4 mmol/L greater than placebo)
        • RRR differed between risk groups & was not proportional to LDL reduction within the range of baseline LDL (1.3-3.2 mmol/L) in IMPROVE-IT. This may represent a fundamental difference from statins (which reduce CV events proportional to LDL reduction), or reflect the low variation in baseline LDL within the study population
    • Achieving an LDL <0.8 mmol/L did not reduce in greater risk of adverse events & was associated with a lower risk of the primary outcome compared to an achieved LDL >1.8 mmol/L