ACCOMPLISH - Amlodipine vs HCTZ added to benazepril in HTN

in

Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. NEJM 2008;359:2417-28.

Bottom line: 

  • When added to an ACE inhibitor, amlodipine reduced the risk of CV events versus HCTZ (NNT 46 over 3 years). Amlodipine produced less dizziness (NNT 20), but far more peripheral edema (NNH 5) than HCTZ.

  • Calcium channel blockers are not superior to other thiazides.

 

Patients (n=11,506)

  • Included
    • HTN
    • High CV risk, defined as hx of any of the following:
      • Existing CVD: Stroke, ACS/MI, PAD, prior revascularization
      • LVH
      • CKD
      • Diabetes
  • Typical study patient
    • Age 68 y
    • Female 40%
    • Prior CVD
      • Stroke 13%
      • MI 24%, unstable angina hospitalization 12%
      • Coronary revascularization 36%
    • Other CV risk factors
      • Smoker 11%
      • LVH 13%
      • eGFR <60 18%, other renal disease 6%
      • Diabetes 60%
      • Dyslipidemia 74%
    • BP 145/80 mm Hg (baseline, treated or untreated)
    • eGFR 79
    • Meds
      • Antiplatelet 65%
      • Statin 68%

Interventions

  • All: Benazepril, plus addition of non-ACEI/CCB/thiazide BP-lowering med after maxing out study meds to achieve target BP)
    • Initial: 20 mg daily
    • After 1 month: Increased to 40 mg daily
  • Amlodipine
    • Initial: 5 mg daily
    • Increased to max 10 mg daily to achieve BP <140/90 (or <130/80 if diabetes/CKD)
      • 61% receiving this dose @ month 6
  • Hydrochlorothiazide (HCTZ)
    • Initial: 12.5 mg daily
    • Increased to max 25 mg daily to achieve BP <140/90 (or <130/80 if diabetes/CKD)
      • 60% received this dose @ month 6

Results @ ~3 years

  • Achieved SBP ~132 with amlodipine vs ~133 mm Hg with HCTZ (SBP 0.9 mm Hg lower with amlodipine)
    • Office BP <140/90: 75% vs 72%
  • Death: 4.1% vs 4.5%, hazard ratio (HR) 0.90 (0.76-1.07)
  • Primary outcome (composite of: CV death, non-fatal MI, stroke, unstable angina hospitalization, coronary revascularization, or resuscitation after sudden cardiac arrest): 9.6% vs 11.8% (NNT 46), HR 0.80 (0.72-0.90)
    • CV death: 1.9% vs 2.3%, HR 0.80 (0.62-1.03)
    • MI: 2.2% vs 2.8%, HR 0.78 (0.62-0.99)
    • Stroke: 1.9% vs 2.3%, HR 0.84 (0.65-1.08)
    • Coronary revascularization: 5.8% vs 6.7%, HR 0.86 (0.74-1.00)
  • Study drug discontinuation: 28.8% vs 31.2%
  • Specific adverse effects
    • Dizziness: 20.7% vs 25.4% (NNT 22)
    • Hypotension: 2.5% vs 3.6%
    • Peripheral edema: 31.2% vs 13.4% (NNH 5)
    • Hypokalemia: 0.1% vs 0.3%

Generalizability

  • Patients in this trial were either "secondary CV prevention" or high-risk "primary CV prevention" patients, so absolute benefit of amlodipine over HCTZ likely lower in a population with lower baseline CV risk
  • Interventions
    • HCTZ is arguably the least effective available thiazide diuretic; therefore, this trial cannot be extrapolated to conclude that amlodipine is superior to other thiazides, particularly chlorthalidone or indapamide when added to an ACE inhibitor
    • Non-comparable doses: Amlodipine 5-10 mg represents the "mid to high" dose range for this agent, whereas HCTZ 12.5-25 mg represents the "low to mid" dose range
      • This likely explains the small but significant difference between groups in mean BP & % of patients achieving target BP

Internal validity

  • Low risk of allocation, performance & detection bias
    • Central allocation; patients, personnel & outcome adjudicators unaware of allocated treatment
    • However: Given high rate of peripheral edema with amlodipine, likely that a sizable portion of patients and clinicians were unblinded to treatment allocation. The effect of this on risk of performance bias is unclear, but likely minimal
  • Low risk of attrition bias
    • Analyzed by intention-to-treat; low loss-to-follow-up (1%) with similar time on treatment in both groups
  • Other: Study stopped early due to benefit based on pre-defined stopping rule
    • This is unlikely to have a meaningful impact on the results as primary outcome results based on >1200 events

Other studies

  • ALLHAT is the major trial that seems to conflict with ACCOMPLISH:
    • Randomized 33,357 adults (55+ y) with BP 140-180/90-110 + high CV risk (existing atherosclerotic CVD, LVH, T2DM, HDL <0.90 mmol/L, or smoker) to chlorthalidone vs amlodipine vs lisinopril for a mean 4.9 years
    • Achieved SBP: ~134 vs ~135 vs ~136 mm Hg
    • Chlorthalidone vs amlodipine: No difference between any group in primary outcome (fatal coronary event or MI) or individual CV outcomes, except lower lower risk of HF incidence (NNT 40) & HF hospitalization (NNT 53) with chlorthalidone
  • A meta-analysis of 7 RCTs comparing diuretics vs CCB (n=51,450), driven largely by ACCOMPLISH & ALLHAT, found no difference in rates of major CV events
  • In my opinion, the above studies suggest that HCTZ is inferior to chlorthalidone. No RCT has ever compared effect of HCTZ vs chlorthalidone on CV events, so only low-quality evidence exists evaluating this theory:
    • Indirect comparison by network meta-analysis suggests that HCTZ may indeed be inferior to chlorthalidone for reduction in CV events;
    • Small RCT showed that chlorthalidone produces greater reduction in 24h & nighttime BP (which is more strongly associated with CV events than office BP) vs HCTZ despite similar office BP lowering;
    • A large administrative cohort study found no difference in CV events between chlorthalidone & HCTZ.