HOPE-3 (statin)

in

Yusuf S, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;online

Clinical Question

In patients without CVD with 1+ CV risk factors, does the indiscriminate use of a statin irrespective of LDL reduce the risk of CVD?

Bottom Line

In a population of patients without CVD with a ~1% annual risk of CVD/MI/stroke at baseline, a fixed "medium" dose of rosuvastatin lowered this risk by ~25% to 0.75%/year. These results are consistent with previous trials of statins in primary prevention.

Design

2x2 factorial, allocation-concealed RCT with "everybody" blinded, low loss-to-follow-up (<1%), analyzed using the intention-to-treat population.

Special notes:

  • Pre-enrollment run-in phase: Single-blind treatment with both HOPE-3 active treatments (BP-lowering & statin) x4 weeks. Advanced to randomization if:
    • Took at least 80% of doses
    • Tolerated regimen without unacceptable adverse events
  • Change to pre-defined outcomes:
    • Single primary outcome changed to 2 co-primary outcomes (done before investigators saw unblinded data)

Patients and Setting

  • 21 countries, 228 centers
  • April 2007 - November 2010
  • Included:
    1. Men 55+ y/o and women 65+ y/o + 1 additional CV risk factor:
      • FHx: Premature CHD in 1o-degree relative (age <55 in men or <65 in women)
      • SHx: Current/recent smoking (regular tobacco within 5 years)
      • O/E: Waist/hip ratio >89 in men and >84 in women
      • Labs:
        • Low HDL (<1.0 mmol/L in men, <1.3 mmol/L in women)
        • Renal dysfunction (microalbuminuria, eGFR <60 mL/min or SCr >124 micromol/L)
        • Dysglycemia (impaired fasting glucose or glucose tolerance test, but not diabetes requiring more than 1 oral antihypoglycemic)
    2. Women 60-64 y/o with 2 additional CV risk factors
    • NOTE: total cholesterol, non-HDL & LDL NOT included as CV risk factors for eligibility, & no minimum criteria for enrollment
  • Excluded:
    • PMHx:
      • Manifest atherosclerotic CVD
      • Clear indication or contraindication for statin &/or ACEI/ARB/thiazide, as determined by subject's own local MD
        • Chronic liver disease or abnormal liver enzymes (i.e. ALT or AST >3x ULN)
        • Inflammatory muscle disease or CK >3x ULN
    • Concurrent meds:
      • Statin or fibrate (patients taking other cholesterol-lowering drugs could be enrolled)
  • 14,682 entered run-in phase -> 12,705 (86.5%) enrolled
  • Average patient:
    • 65.7 y/o
    • 46% female
    • Race: 29% Chinese, 27% Hispanic, 20% White, 15% South Asian, <2% Black
    • Enrollment CV risk factors:
      • 26% with FHx premature CHD
      • 28% current/recent smoking
      • 87% with elevated waist/hip ratio (mean BMI 27)
      • 36% with low HDL
      • <3% with renal dysfunction
      • 13% with impaired glucose, 6% with diabetes
      • BP 138/82 mm Hg (38% with history of HTN)
      • SCr: 80 micromol/L
      • Lipids: Total cholesterol 5.2 mmol/L, HDL 1.2 mmol/L, LDL 3.3 mmol/L
      • Fasting plasma glucose: 5.3 mmol/L
      • Baseline meds
        • Any BP-lowering drug 22%
          • CCB 15%
          • Beta-blocker 8%
        • ASA 11%

Intervention and Control

  • Intervention: Rosuvastatin 10 mg PO daily
    • Adherence: 88% @ 1 year, 84% @ 3 years, 75% @ 5 years
  • Control: Matching placebo
    • Adherence: 88% @ 1 year, 83% @ 3 years, 73% @ 5 years
  • Co-interventions common to both groups:
    • Randomized to candesartan 16 mg + hydrochlorothiazide 12.5 mg PO once daily or placebo
    • Individualized structured lifestyle advice
  • Follow-up:
    • Visits q6 weeks x6 months, then q6 months
      • Monitoring parameters: Adherence, safety, trial outcomes

Outcomes

  • @ median follow-up 5.6 years
  • Mean LDL 1 mmol/L lower with rosuvastatin vs control @ 1 year
  • Efficacy: Statistically significant reduction in both co-primary outcomes & a number of secondary outcomes. The effect on CV death/MI/stroke translates to a 1.1% absolute risk reduction at 5.6 years (i.e. a number needed to treat of 91 over 5.6 years, or ~500 per year)
  • Safety:
    • No signal of clinically-relevant increased risk of cancer, dementia/neuropsychiatric abnormalities, changes in LFTs, or diabetes
    • 2 vs 1 cases of rhabdo; consistent with previous statin trials
    • Absolute risk increase of 1.1% in muscle pain/weakness with rosuvastatin 10 mg vs placebo that did not translate into a greater risk of drug discontinuation
  • Subgroup analyses: None of 16+ significant. In other words, the relative effects (relative risk reduction) of statins on CVD events are consistent across the study population.

Outcomes in HOPE-3 statin trial