SHIFT

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Swedberg K et al. "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 2010. 376(10):875-885.
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Clinical Question

In patients with symptomatic HFrEF (NYHA II-IV; LVEF ≤ 35%) with hospitalization for heart failure within the preceding year and resting heart rate of ≥ 70bpm despite maximal medical therapy including beta blockers, does the addition of the sinus node inhibitor ivabradine result in improved heart failure-related mortality or hospitalization compared to placebo?

Bottom Line

In patients with symptomatic HFrEF (NYHA II-IV: LVEF ≤ 35%) with hospitalization for heart failure within the preceding year on contemporary medical therapy (i.e., ACE/ARB, beta blockers, and aldosterone antagonists) with resting heart rate ≥ 70bpm, the addition of ivabradine resulted in a 5% absolute reduction in heart failure mortality or hospitalization at 2 years. The benefit of ivabradine was driven both by a 5% absolute reduction in heart failure hospitalization as well as a 2% absolute reduction in heart failure mortality.

Major Points

On the strength of large RCTs including MERIT-HF and COPERNICUS demonstrating clear mortality benefit, beta blockers have become standard of care in patients with symptomatic heart failure with reduced ejection fraction (HFrEF). A major mechanism by which these agents are thought to provide benefit is by reducing myocardial oxygen demand by lowering heart rate through antagonism of sympathetic receptors in myocardial pacemaking tissue. This mechanism is supported by studies demonstrating strong associations between increasing resting heart rate (HR) and cardiovascular outcomes in patients with ischemic cardiomyopathy.[1]

Despite their beneficial effects, beta blockers have some untoward effects which become more pronounced in patients with HFrEF, including hypotension and decreased inotropy. The novel sinus node modifying agent ivabradine lowers heart rate by inhibiting the "funny current" (If) channel which is critical in determining the automaticity rate of pacemaking cells in the sinoatrial node. Given this very targeted mechanism of action, ivabradine may allow for further HR lowering despite maximally-tolerated doses of beta blocker therapy. The earlier BEAUTIFUL trial investigating ivabradine in patients with ischemic cardiomyopathy gestured at this potential by demonstrating that those with a HR ≥ 70bpm at study entry treated with ivabradine had lower rates of MI and coronary revascularization. Whether these benefits could be shown more definitively in patients with HFrEF of any cause with persistent HR ≥ 70bpm at baseline while on guideline-directed therapy was unknown.

The 2010 Systolic Heart failure treatment with the If inhibitor Ivabradine Trial (SHIFT) randomized 6558 patients with symptomatic HFrEF (NYHA II-IV; LVEF ≤ 35%) with hospitalization for heart failure within the preceding year and resting HR ≥ 70bpm despite maximally-tolerated medical therapy (i.e., ACE/ARB, beta blocker, aldosterone antagonist) to ivabradine versus placebo in order to investigate whether additional HR reduction with ivabradine would lead to improvement in a primary outcome of heart failure-related hospitalization or mortality. At a median follow-up of nearly 2 years, ivabradine therapy was associated with a 5% absolute reduction in the primary endpoint, driven by both a 5% absolute reduction in hospitalization for heart failure and a 2% absolute reduction in heart failure mortality (with trends to improved all-cause mortality and cardiovascular mortality). Both a prespecified subgroup analysis and a later formal analysis of these findings demonstrated that benefit was tied largely to HR reduction, as benefit was greatest in patients with resting HR > 75bpm and good HR response to ivabradine. [2] Overall, ivabradine was well-tolerated, with only a modest increase in symptomatic bradycardia with ivabradine and a higher incidence of total adverse events in the placebo group. Notably, only 26% of patients in SHIFT were on guideline-based target doses of beta blocker and only 56% of patients were on at least half-target doses at inclusion. Given that the benefits of ivabradine were somewhat attenuated in the subgroup of patients on at least half-dose beta blocker therapy, this raises the question of whether ivabradine truly benefits patients already on target dose beta blocker therapy.

Nevertheless, primarily on the strength of SHIFT, ivabradine is now recommended by ESC guidelines as additional therapy for patients with HFrEF (LVEF ≤ 35%), persistent NYHA II-IV symptoms, and resting HR ≥ 70bpm despite maximal medical therapy including ACE/ARB, beta blocker, and aldosterone antagonist. These guidelines also recommend consideration of ivabradine in patients with HFrEF and beta blocker intolerance. Notably, ivabradine was only FDA approved in the US for heart failure in 2015; as a result, the ACC/AHA has yet to comment on ivabradine in their heart failure guidelines.

Guidelines

European Society of Cardiology HF Guidelines 2012[3]

  • Ivabradine should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤ 35%, a heart rate remaining ≥ 70bpm and persisting symptoms (NYHA class II-IV) despite treatment with evidence-based dose of beta blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB) (class IIa, level B).
  • Ivabradine may be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤ 35% and a heart rate ≥ 70bpm who are unable to tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). (class IIb, level C).

Design

  • Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
  • Patients randomized 1:1 to ivabradine versus placebo
    • Ivabradine (N=3268)
    • Placebo (N=3290)
  • Setting: 677 centers in 37 countries
  • Enrollment: 10/3/2006 - 3/31/2010
  • Median follow-up: 22.9 months
  • Analysis: Intention-to-treat
  • Primary Outcome: Heart failure death or hospitalization

Population

Inclusion Criteria

  • 18 years or older
  • Sinus rhythm on at least 2 consecutive visits
  • Stable chronic heart failure ≥ 1 month
  • NYHA class II-IV symptoms
  • Hospitalization for heart failure within 1 year
  • LVEF ≤ 35% within last 3 months
  • On maximally tolerated guideline-directed therapy (ACE/ARB, beta blocker and/or aldosterone antagonist)

Exclusion Criteria

  • Congenital heart disease
  • Severe primary valvular heart disease
  • Myocardial infarction within preceding 2 months
  • Ventricular or atrioventricular pacing requirement ≥ 40%
  • Atrial fibrillation or flutter
  • Symptomatic hypotension or SBP < 85mmHg
  • Stroke or cerebral ischemia within preceding month
  • Sick sinus syndrome, sinoatrial block, or second-degree or greater atrioventricular block
  • ICD shock within previous 6 months
  • Severe or uncontrolled HTN (SBP > 180mmHg or DBP > 110mmHg)
  • Moderate or severe liver disease, severe renal disease, or anemia

Baseline Characteristics

From the placebo group.

  • Demographics: age 60 years, 77% male, 89% white
  • Comorbidities: 18% active smoker, BMI 28.0, 56% previous MI, 66% HTN, 31% DM, 9% CVA, 8% AF/flutter
  • Cardiac parameters: Heart rate 80bpm, SBP 121 mmHg, LVEF 29%, eGFR 74.8
  • Heart failure characteristics: 49% NYHA II, 50% NYHA III, duration of CHF 4.2 years, 67% ICM
  • Medications: 90% beta blocker, 78% ACE inhibitor, 14% ARB, 83% diuretic, 59% aldosterone antagonist, 22% cardiac glycoside
  • Devices: 1% CRT, 4% ICD
  • Beta blocker use: 26% at target dose, 56% at half target dose, 45% uptitration limited by hypotension, 32% uptitration limited by fatigue, 43% intolerant due to COPD/asthma, 20% intolerant due to hypotension

Interventions

  • Randomization preceded by 14 day run-in period to confirm inclusion/exclusion criteria
  • Patients and investigators blinded to treatment allocation
  • Stratification done by center and by use of beta blocker at inclusion
  • Ivabradine started at 5mg twice daily with increase to 7.5mg twice daily or decrease to 2.5mg twice daily at minimum of 14 day intervals for goal HR 51-60bpm
  • Starting at day 28, follow up visits occurred every 4 months until study closure

Outcomes

Comparisons are ivabradine vs. placebo

Primary Outcomes

Heart failure death or hospitalization
793 (24%) vs. 937 (29%); HR 0.82 [95% CI 0.75-0.90]; p < 0.0001

Secondary Outcomes

All-cause mortality
503 (16%) vs. 552 (17%); HR 0.90 [95% CI 0.80-1.02]; p = 0.092
Cardiovascular mortality
449 (14%) vs. 491 (15%); HR 0.91 [95% CI 0.80-1.03]; p = 0.128
Heart failure mortality
113 (3%) vs. 151 (5%); HR 0.74 [95% CI 0.58-0.94]; p = 0.014
Hospitalization for heart failure
514 (16%) vs. 672 (21%); HR 0.74 [95% CI 0.66-0.83]; p < 0.0001
Improvement in NYHA class
887 (28%) vs. 776 (24%); p = 0.001
Heart rate reduction at 1 year
9.1bpm [95% CI 8.5-9.7]

Subgroup Analyses

Patients receiving at least 50% of target dose beta blocker

Cardiovascular death or hospitalization for heart failure
HR 0.90 [95% CI 0.77-1.04]; p = 0.155
Hospitalization for heart failure
Treatment difference 19% (in favor of ivabradine); HR 0.81 [95% CI 0.67-0.97]; p = 0.021

Baseline Heart Rate (interaction p = 0.029)

< 77 bpm (N=3144)
339 (21.4%) vs. 356 (22.8%); HR 0.93 [95% CI 0.80-1.08]
≥ 77 bpm (N=3357)
454 (27.4%) vs. 581 (34.2%); HR 0.75 [95% CI 0.67-0.85]

Adverse Events

Serious adverse events
1450 (45%) vs. 1553 (48%); p = 0.025
Symptomatic bradycardia
150 (5%) vs. 32 (1%); p < 0.0001
Asymptomatic bradycardia
184 (6%) vs. 48 (1%); p < 0.0001
Phosphenes (visual anomalies)
89 (3%) vs. 17 (1%); p < 0.0001

Criticisms

  • Only 26% of subjects on target doses of beta blocker and only 56% of patients on at least half-target doses of beta blocker. Although this is presumably due to beta blocker intolerance, an element of beta blocker underuse may have overestimated the benefit of ivabradine.
  • Effects of ivabradine attenuated in group of patients on at least 50% target dose of beta blocker, raising question of whether the benefit of ivabradine may be limited to patients with complete or partial beta blocker intolerance.

Funding

  • Study sponsor responsible for data management and final analyses
  • Members of the medical and scientific departments of the study sponsor supported the work of the executive committee

Further Reading