HOPE-3 (BP lowering)

in

Lonn EM, et al. Blood-pressure 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 fixed "medium" dose of candesartan + HCTZ irrespective of BP reduce the risk of CVD?

 

Bottom Line

In this population of patients without CVD at mostly intermediate risk, a fixed "medium" dose of candesartan + HCTZ did not lower the risk of CVD over ~5 years.

Possible explanations for the results of this study include already-low baseline CV risk and BP and suboptimal BP-lowering agents as intervention (amlodipine chlorthalidone, &/or an ACEI would have been more appropriate based on prior evidence). As a result, this study complements, rather than conflicts with, similar studies such as the well-publicized SPRINT trial.

 

Design

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

Special notes:

  • Pre-enrollment run-in phase: Single-blind treatment with both HOPE-3 active treatments (BP- & cholesterol-lowering) x4 weeks. Advanced to randomization if:
    • Took at least 80% of doses
    • Tolerated regimen without unacceptable adverse events
  • Power calculation: Based on described assumptions, inclusion of 12,700 participants should rule out relative risk reduction by 22.5% with candesartan/hydrochlorothiazide
  • 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
  • Inclusion criteria:
    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) Women 60-6
    2. Women 60-64 y/o with 2 additional CV risk factors
    • NOTE: BP not included as a CV risk factor for eligibility, & no minimum BP criteria for enrollment
  • Exclusion criteria:
    • PMHx:
      • Manifest atherothrombotic CVD
      • Clear indication or contraindication for statin &/or ACEI/ARB/thiazide, as determined by subject's own local MD
      • Symptomatic hypotension
        • Chronic liver disease or abnormal liver enzymes (i.e. ALT or AST >3x ULN)
        • Severe renal impairment (calculated CrCl <30 mL/min/1.73 m^2 or SCr >264 micromol/L
        • Inflammatory muscle disease or CK >3x ULN
        • Significant psychiatric illness, senility, dementia, ETOH or substance abuse
    • Concurrent meds:
      • Cyclosporine, or a condition likely to result in organ transplant & need for cyclosporine
      • ACEI, ARB, thiazide
      • Statin or fibrate (patients taking other cholesterol-lowering drugs could be enrolled)
    • Enrolled in other drug study
  • 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 1.17 mmol/L, LDL 3.29 mmol/L
      • Fasting plasma glucose: 5.3 mmol/L
      • Baseline meds
        • Any BP-lowering drug 22%
          • CCB 15%
          • Beta-blocker 8%
        • ASA 10%

 

Intervention and Control

  • Intervention: Single-tablet combination of candesartan 16 mg + hydrochlorothiazide 12.5 mg PO once daily
    • Adherence: 88% @ 1 year, 84% @ 3 years, 75% @ 5 years, 77% @ end of trial
    • Mean BP decrease from baseline: 10/6 mm Hg
  • Control: Matching placebo
    • Adherence: 88% @ 1 year, 83% @ 3 years, 75% @ 5 years, 76% @ end of trial
    • Mean systolic BP decrease from baseline: 4/3 mm Hg
  • Co-interventions common to both groups:
    • Randomized to rosuvastatin 10 mg PO daily or placebo
    • Individualized structured lifestyle advice
  • Follow-up:
    • Visits q6 weeks x6 months, then q6 months
      • Monitoring parameters: Adherence, safety, trial outcomes
    • BP measurement
      • q visit x1 year, then q1 year
      • Using Omron automated device
      • Average of 2 measurements after 5 min of quiet rest

 

Outcomes

  • @ median follow-up 5.6 years
  • Mean BP 6/3 mmHg lower with intervention vs control
  • No statistically significant difference in any primary or secondary outcome
  • Subgroup analyses:
    • 16+ performed
    • Significant difference in efficacy based on tertile of SBP (<132, 132-143, >143), p for interaction = 0.02 & 0.009, respectively, for each coprimary outcome
      • Benefit if baseline SBP > ~140
      • No effect, or possible harm if baseline SBP <140
    • No difference in effect based on other subgroups (baseline diastolic BP, +/- rosuvastatin, age, baseline CV risk or LDL, etc)

Outcomes in HOPE-3 BP-lowering trial

 

Key Considerations

Patients: This trial evaluated a "minimal investigation" preventative philosophy of management. Patient were enrolled based on age and presence of 1+ other CV risk factors; CV risk calculators were not used to determine study eligibility. Individual risk scores have varying impact on CV risk (e.g. a 30-year smoking history increases CV risk substantially more than a fasting plasma glucose of 6.5 mmol/L). In practice, a more nuanced assessment of CV risk incorporating a CV risk calculator, other conditions and medications with impact on CV risk will better capture patients who may benefit from BP lowering.

Intervention: The "neutral results" of this trial may be due to suboptimal BP-lowering therapy. For thiazides, far more robust evidence of lowering CV events exists for chlorthalidone (ALLHAT, SHEP) & indapamide (ADVANCE, HYVET, PROGRESS]) than HCTZ, in addition to greater reductions in 24h BP on ambulatory monitoring. Candesartan has the advantage of not causing an "ACEI cough", but also has a less-robust evidence base than ACE inhibitors such as ramipril (used in the original HOPE trial).

 

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: 4 May 2016