BP lowering: High-dose monotherapy or low-dose combo?

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Law MR, et al. Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomised trials. BMJ 2003;326:1427.

Bottom-line: In patients with hypertension, addition of an extra BP-lowering agent at a low dose provides greater BP-lowering with fewer side effects than increasing the dose of a single agent.

Each additional low-dose BP-lowering drug reduces BP by an extra ~6/3 mm Hg & cause side effects in an extra 1 out of every ~50 people. Conversely, doubling the dose of a BP-lowering agent will further reduce BP by ~2/1 mm Hg & cause side effects in an extra 1 out of every 12-30 people.

 

Design summary

  • Systematic review with meta-analysis of 354 randomized controlled trials (RCTs) including 39,879 patients receiving active treatment & 15,817 receiving placebo
    • Databases searched: MEDLINE, Cochrane Library, Web of Science
    • Search date: Unclear (before June 2003)
    • Study eligibility criteria: Double-blind RCTs of at least 2-weeks duration evaluating dose response + effect of combination of antihypertensives

Patients & interventions

  • Key baseline characteristics
    • Age, mean: 53 y
    • BP, median: 154/97 mm Hg
  • Drug classes included: ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, thiazide diuretics

Outcomes at 2-12 weeks

  • BP lowering (similar across all 5 drug classes at comparable doses)
    • By dose
      • 1/2 standard dose: ~7/4 mm Hg
      • Standard dose (defined as typical maintenance dose based on British National Formulary, e.g. amlodipine or ramipril 2.5 mg/d): ~9/6 mm Hg
      • Double standard dose: ~11/7 mm Hg
      • In other words, doubling the dose of BP-lowering therapy further lowered BP by ~2/1 mm Hg
    • By # of drugs from different classes at 1/2 standard dose
      • 1 drug: ~7/4 mm Hg
      • 2 drugs: 13/7 mm Hg
      • 3 drugs: 20/11 mm Hg
      • In other words, BP-lowering drugs have additive efficacy
  • % with adverse effects
    • By class based on dose
      • ACE inhibitor: ~4% at all doses
      • ARB: ~0-2% at all doses
      • Beta-blocker
        • 1/2 standard dose: ~5-6%
        • Standard dose: ~7-8%
        • Double standard dose: ~9-10%
      • Calcium-channel blocker
        • 1/2 standard dose: 2%
        • Standard dose: 8%
        • Double standard dose: 15%
      • Thiazide diuretic
        • 1/2 standard dose: 2%
        • Standard dose: 10%
        • Double standard dose: 18%
    • By # of drugs
      • 1 drug: ~5%
      • 2 drugs: 7-8%
      • 3 drugs: Not studied