SHIFT - Ivabradine for heart failure with reduced ejection fraction

Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-85.

Bottom-line: In patients with HFrEF and a resting heart rate >70 bpm despite maximally-tolerated beta-blocker therapy, ivabradine reduced the risk of hospital admissions (NNT 25), mainly by reducing HF-related hospitalization, over ~2 years.

When using ivabradine, monitoring HR via pulse and EKG at baseline and at follow-up is critical to ensure benefit, and to minimize symptomatic bradycardia (NNH 25) and atrial fibrillation (NNH 100). It appears that the higher the baseline HR, the greater the benefit (and likely the lower risk of bradycardia).

 

Patients (n=6558)

  • Inclusion
    • Age 18+ y
    • Stable symptomatic HF for at least 4 weeks
    • LVEF 35% or lower
    • HF hospitalization in the last 12 months
    • Normal sinus rhythm with HR 70+ bpm on 12-lead EKG after 5 min of rest on 2 consecutive visits
  • Exclusion
    • HF etiology of congenital heart disease or primary severe valvular disease
    • MI in last 2 months
    • Implantable pacemaker that's pacing >40% of the day
    • AF/flutter
    • Symptomatic hypotension
    • Drugs: Use of diltiazem or verapamil, class I antiarrhythmics or strong CYP 3A4 inhibitors
  • Screened 7411 -> randomized 6558
  • "Average" patient in the trial
    • Age 60 y
    • Male 76%
    • Duration of HF 3.5 y
    • HF etiology: Ischemic 68%
    • NYHA class: II (~50%), III (~50%)
    • PMHx
      • MI 56%
      • HTN 67%
      • Diabetes 30%
      • AF/flutter 8%
    • BP 122/76 mm Hg
    • HR 80 bpm
    • LVEF 29%
    • eGFR 75 mL/min*1.73 m^2
    • Meds
      • Beta-blocker ~90% (26% on target dose, 56% on at least 1/2 target dose)
      • ACEI ~80%, ARB 14%
      • Mineralocorticoid antagonist ~60%
      • Diuretic 84%
      • Digoxin 22%
      • Devices: ICD 3%, CRT 1%

Intervention & control

  • I: Ivabradine
    • Initial dose of 5 mg PO BID
    • After 14 days:
      • If HR >60 bpm, increased to 7.5 mg PO BID
      • If HR 50-60 bpm, kept on 5 mg PO BID
      • If HR <50 bpm or symptomatic bradycardia, dose reduced to 2.5 mg PO BID
    • At each subsequent follow-up, above algorithm used to titrate between 2.5-7.5 mg PO BID
  • C: Matching placebo

Results @ median 1.9 years

  • HR
    • @ 1 month: Ivabradine 64 bpm, placebo 75 bpm
    • @ 2-3 years: 67 vs 75 bpm
  • Significant reduction with ivabradine in:
    • Serious adverse events: Ivabradine 45%, placebo 48% (p=0.025)
    • Primary outcome (CV death or hospital admission for HF): 24% vs 29% (hazard ratio 0.82, 0.75-0.90), NNT 20
    • Hospital admission: 38% vs 42% (HR 0.90, 0.82-0.96), NNT 25
      • For HF: 16% vs 21%
    • Unclear effect on death
      • No statistically significant difference in death (16% vs 17%. HR 0.90, 0.80-1.02) or CV death: 14% vs 15% (HR 0.91, 0.80-1.03)
      • Reduction in death from HF: 3% vs 5% (HR 0.74, 0.58-0.94)
    • Significant increase with ivabradine in:
      • Symptomatic bradycardia: 5% vs 1%, NNH 25
      • Asymptomatic bradycardia: 6% vs 1%, NNH 20
      • Atrial fibrillation: 9% vs 8%, NNH 100
      • Blurred vision: 1% vs <1%, NNH 100
      • Phosphenes: 3% vs 1%, NNH 50
  • Subgroup analyses demonstrated a significant interaction between baseline HR 77 bpm or greater versus <77 bpm and effect on the primary outcome. Greater relative benefit was seen in patients with a higher baseline HR.

Generalizability

  • Patients included in this trial overall had HFrEF of ischemic and non-ischemic origin with NYHA functional class II or III
  • Use of background medical therapies for HFrEF was fairly good, although very few patients were optimized on beta-blockers, with the most common reasons cited as hypotension and fatigue

Internal validity

  • Low risk of allocation, performance and detection bias
    • Computer-generated randomization with central, automated allocation and blinding with use of identical placebo)
  • Low risk of attrition bias
    • Loss-to-follow-up <1%
    • Intention-to-treat analysis

Other studies

  • The BEAUTIFUL trial, which came out before SHIFT, evaluated the use of ivabradine in patients with CAD and LV dysfunction with a heart rate of 60 bpm or greater
    • Patients were quite similar to those in the SHIFT trial with a mean HR of 72 bpm and 84% with HFrEF NYHA class II or III
    • In the overall population studied in BEAUTIFUL, ivabradine did not reduce the risk of CV events
    • In a subgroup of patients with HR >70 bpm (mimicking the SHIFT population), there was no reduction in the primary outcome or any HF-related outcome.
  • A pooled analysis of BEAUTIFUL and SHIFT showed results consistent with the SHIFT trial in patients with HFrEF and HR of 70 bpm or more.
  • The SIGNIFY trial, which was published after SHIFT, evaluated ivabradine in patients with CAD without HF with a HR of 70 bpm or greater
    • Patients had stable CAD, no HF, a mean HR of 77 bpm, and a mean LVEF of 56%
    • All analyses of SIGNIFY demonstrated no benefit on CV outcomes, with a possible increase in HF-related hospital admission (HR 1.20, 0.99-1.46), and an increased risk of the primary CV outcome in patients with angina CCS class II-IV at baseline
    • In this population, ivabradine increased the risk of adverse events (NNH 14), symptomatic bradycardia (NNH 15), phosphenes (NNH 20) and blurred vision (NNH 125)
    • SIGNIFY therefore solidifed that ivabradine has no role in CAD without HF.
  • None of the trials (BEAUTIFUL, SHIFT, SIGNIFY) enrolled patients with HFpEF. The role of ivabradine in HFpEF is therefore unknown.