HPS - Statins in secondary prevention & patients with diabetes

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: A randomised placebo controlled trial. Lancet 2002;360:7-22.

Bottom-line: In patients with existing CVD or diabetes, statin therapy reduced the risk of death (NNT 56) & all major vascular events (NNT 19) over 5 years.

In this population that initially tolerated simvastatin during a 4-6 week run-in phase & was not taking other lipid-lowering therapy, moderate-dose simvastatin did not increase the risk of cancer, cognitive impairment, liver enzyme abnormalities, myalgias or myopathy. 

 

Patients (n=20,536)

  • Included
    • Age 40-80 y
    • Total cholesterol (non-fasting) 3.5+ mmol/L
    • High risk for coronary death based on a past medical history of any of:
      • CAD (past ACS, stable angina, CABG or PCI)
      • Cerebrovascular disease (non-disabling non-hemorrhagic stroke, TIA, carotid endarterectomy)
      • PAD (intermittent claudication)
      • Other arterial surgery or angioplasty
      • Diabetes (type 1 or 2)
      • None of the above, but >65 y/o male with treated HTN
  • Excluded
    • Statin "clearly indicated"
    • Severe HF
    • Chronic liver disease (cirrhosis, hepatitis or ALT >1.5x ULN)
    • Creatinine >200 umol/L
    • Muscle disease (inflammatory muscle disease or CK >3x ULN)
    • Concurrent treatment with cyclosporine, fibrates or high-dose niacin
  • 63,603 screened -> 32,145 entered run-in -> 20,536 randomized -> 20,469 analyzed
  • "Typical" study patient
    • Age >64 y 46%
    • Female 25%
    • PMHx
      • MI 41%
      • Other CAD 24%
      • No coronary hx 35%
        • Cerebrovascular disease 9%
        • PAD 13%
        • Diabetes 19%
        • HTN as only inclusion criterion 1%
    • Lipids: Total cholesterol 5.9 mmol/L, LDL 3.4 mmol/L, apoB 1.14 g/L
    • Meds (CAD subgroup)
      • ASA 63% (77%)
      • ACEI 20% (10%)
      • Beta-blocker 26% (23%)

Interventions

  • I: Simvastatin 40 mg PO once daily
    • Adherence to >80% of doses: 89% @ 1 y, 82% @ 5 y
  • C: Matching placebo
    • Open-label statin use: 4% @ 1 y, 32% @ 5 y

Results @ mean 5 years

  • LDL
    • @ baseline: 3.4 mmol/L
    • Difference: -1.3 mmol/L @ 1 y, -0.7 mmol/L @ 5 y
  • Death: Simvastatin 12.9%, placebo 14.7% (hazard ratio 0.87, 0.81-0.94), NNT 56
  • Major vascular event (components below): 19.8% vs 25.2% (HR 0.76, 0.72-0.81), NNT 19
    • Non-fatal MI or coronary death: 8.7% vs 11.8%
    • Stroke: 4.3% vs 5.7%
    • Coronary revascularization: 5.0% vs 7.1%
    • Non-coronary revascularization: 4.4% vs 5.2%
  • Adverse effects
    • Cancer: 7.9% vs 7.8%
    • Cognitive impairment: 23.7% vs 24.2%
    • ALT >4x ULN: 0.4% vs 0.3%
    • Unexplained muscle pain/weakness reported at least once: 32.9% vs 33.2%
    • CK
      • 4-10x ULN: 0.2% vs 0.1%
      • >10x ULN: 0.11% vs 0.06%
    • Subgroup analyses demonstrated consistent relative risk reduction in major vascular event across different high-risk inclusion criteria, so absolute benefit dependent on baseline risk. 5-year risk in placebo group (NNT with statin) in relevant subgroups:
      • CAD only: 22.5% (NNT 16)
      • No CAD
        • Cerebrovascular disease: 23.6% (NNT 18)
        • PAD: 30.5% (NNT 14)
        • Diabetes: 18.6 (NNT 23)

Generalizability

  • Represents a wide spectrum of patients with existing vascular disease or diabetes with poor use of other secondary CV prevention interventions, particularly in the CAD subgroup
  • Run-in phase: Placebo x4 weeks, then simvastatin 40 mg/d x4-6 weeks
    • To ensure long-term adherence + "responsiveness" to LDL lowering
    • 36% who entered run-in did not undergo randomization, mostly due to unwillingness or inability to adhere for a planned 5 years
    • Therefore, represents a population that did not have intolerable adverse events after a month of statin therapy

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Central telephone randomization

    • Patients, clinicians, adjudicators unaware of treatment allocation

    • Loss-to-follow-up <0.5%

    • Intention-to-treat analysis

  • High risk of contamination bias

    • By year 5, 32% of patients in placebo group were receiving an open-label statin

    • This acts as a conservative bias, as it attenuates the apparent benefit of statin therapy