SHIFT - Ivabradine for heart failure with reduced ejection fraction
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
CRT implanted in last 6 months
Implantable pacemaker that's pacing >40% of the day
Permanent 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.