Ivabradine
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Reduction of HF hospitalisation in stable, symptomatic chronic HFrEF | Adults with LVEF ≤35%, sinus rhythm, resting HR ≥70 bpm, on max-tolerated beta-blocker (or contraindication to beta-blockade) | Adjunctive to GDMT | FDA Approved (2015) |
| Stable symptomatic heart failure due to dilated cardiomyopathy | Pediatric patients ≥6 months in sinus rhythm with elevated heart rate | Adjunctive | FDA Approved (2019) |
Ivabradine is a pure heart-rate-lowering agent — it slows the sinoatrial node without affecting contractility, blood pressure, or ventricular repolarisation. Its niche in adult heart failure is narrow but well defined: the SHIFT trial population of HFrEF patients with persistent resting tachycardia (HR ≥70 bpm) despite maximally tolerated beta-blockade. In SHIFT (n=6,558 randomised), ivabradine reduced the primary composite of cardiovascular death or hospitalisation for worsening heart failure (hazard ratio 0.82, 95% CI 0.75–0.90, p<0.0001), driven principally by a reduction in HF hospitalisations; there was no significant effect on cardiovascular mortality.
The drug should be reserved for patients meeting the SHIFT trial criteria — in particular, sinus rhythm and a target heart rate that cannot be achieved with optimised beta-blocker therapy. Ivabradine is not a substitute for beta-blockers in HFrEF; the SHIFT subgroup analysis showed diminishing benefit at higher beta-blocker doses, with little if any apparent effect in patients already at guideline-target beta-blocker doses. Ivabradine also offers no benefit in patients with atrial fibrillation, where it may both fail to reduce ventricular rate and increase the risk of new arrhythmia.
Inappropriate sinus tachycardia (IST) — supported by the 2015 HRS expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, IST and vasovagal syncope. Evidence quality: moderate (small RCTs and observational studies).
Postural orthostatic tachycardia syndrome (POTS) — heart-rate selectivity makes it attractive when beta-blockers are not tolerated. Evidence quality: low–moderate.
Postoperative junctional ectopic tachycardia in pediatric cardiac surgery — refractory cases. Evidence quality: low (case series).
Stable angina (chronic coronary syndromes) — approved in Europe (Procoralan) but not in the United States. The SIGNIFY trial in CAD without HF showed no benefit on the primary composite (HR 1.08, 95% CI 0.96–1.20).
Atrial fibrillation rate control — investigational; the BRAKE-AF trial showed ivabradine was less effective than digoxin for permanent AF. Evidence quality: low; not recommended for this purpose.
Dosing
Ivabradine is taken twice daily with food (food delays absorption by approximately 1 hour but increases plasma exposure by 20–40% and reduces variability). The drug is titrated to a target resting heart rate of 50–60 bpm in adults — adjustments are made every two weeks based on the resting heart rate measured at the next visit.
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| HFrEF — standard adult initiation | 5 mg PO BID | 5–7.5 mg PO BID | 7.5 mg BID | Take with food. Reassess HR at 2 weeks Target resting HR 50–60 bpm |
| HFrEF — patients with conduction defects, or where bradycardia could lead to haemodynamic compromise (also “vulnerable adults” per PI) | 2.5 mg PO BID | 2.5–7.5 mg PO BID | 7.5 mg BID | Slower up-titration; check HR before each escalation |
| Resting HR >60 bpm at follow-up | — | Increase by 2.5 mg BID | 7.5 mg BID | Per PI Table 1. Reassess in 2 weeks |
| Resting HR 50–60 bpm | — | Maintain current dose | — | Therapeutic target achieved |
| Resting HR <50 bpm or signs/symptoms of bradycardia | — | Decrease by 2.5 mg BID | — | Per PI: if current dose is already 2.5 mg BID, discontinue therapy |
Pediatric Dosing (Heart Failure due to Dilated Cardiomyopathy, ≥6 months)
Per the Corlanor PI, pediatric dosing is structured by body weight, not age — under 40 kg uses weight-based oral solution, 40 kg or greater uses tablets. The pediatric titration target is at least a 20% reduction in resting heart rate (rather than the adult target of 50–60 bpm).
| Group | Starting Dose | Titration | Maximum Dose | Notes |
|---|---|---|---|---|
| ≥6 months, <1 year, <40 kg | 0.05 mg/kg PO BID | Adjust by 0.05 mg/kg every 2 weeks based on HR/tolerability | 0.2 mg/kg BID | Use oral solution. Take with food. If a dose is missed or spit out, do not give a replacement dose Target ≥20% HR reduction |
| ≥1 year, <40 kg | 0.05 mg/kg PO BID | Adjust by 0.05 mg/kg every 2 weeks | 0.3 mg/kg BID (capped at 7.5 mg BID total) | Oral solution preferred for accurate weight-based dosing |
| ≥40 kg | 2.5 mg PO BID | Adjust by 2.5 mg every 2 weeks | 7.5 mg BID | Tablets or oral solution |
| Bradycardia at the recommended initial dose (any pediatric weight) | — | — | — | Per PI: consider reducing the dose to 0.02 mg/kg BID |
Special Populations
| Population | Recommendation | Notes |
|---|---|---|
| Renal impairment (CrCl 15–60 mL/min) | No adjustment | Renal excretion ~4%; minimal effect on PK |
| Severe renal impairment (CrCl <15 mL/min) | No data; use with caution | Per PI: data not available |
| Mild–moderate hepatic impairment (Child-Pugh A–B) | No adjustment | PK similar to normal hepatic function (per PI) |
| Severe hepatic impairment (Child-Pugh C) | Contraindicated | No data; increased exposure anticipated |
| Older adults / vulnerable adults | Start 2.5 mg BID | Per PI; titrate cautiously based on HR and tolerability |
Per the Corlanor PI, heart-rate reduction with ivabradine is dose- and baseline-dependent: greater absolute reductions occur in patients with higher baseline rates. At recommended doses, expect approximately 10 bpm reduction at rest and during exercise; the effect plateaus at doses above 20 mg twice daily, so no benefit is gained beyond 7.5 mg BID and adverse-event risk increases.
Ivabradine is only effective in sinus rhythm. If a patient develops atrial fibrillation, the drug must be discontinued — it does not control AV-nodal conduction and may worsen the arrhythmia (per Section 5.2 of the PI).
Ivabradine is added after beta-blocker optimisation, not as a substitute. SHIFT enrolled patients on a maximally tolerated beta-blocker (or with a documented contraindication); only 26% were at guideline-target beta-blocker doses at baseline, with hypotension, fatigue, and dyspnoea being the most common reasons for not reaching target.
Avoid grapefruit juice and St. John’s wort (per PI patient-counselling section).
Pharmacology
Mechanism of Action
Ivabradine selectively blocks the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels — predominantly HCN4 — that generate the “funny current” (If) in sinoatrial node pacemaker cells. This current drives the slow diastolic depolarisation that determines spontaneous firing rate. By inhibiting If, ivabradine reduces the slope of diastolic depolarisation and slows sinus rate without affecting myocardial contractility or ventricular repolarisation. In clinical electrophysiology studies, IV ivabradine slowed heart rate by approximately 15 bpm and modestly increased PR and AH intervals (~29 msec and ~27 msec respectively); there is no rate-corrected QT prolongation. Heart-rate reduction is dose- and baseline-dependent and plateaus above approximately 20 mg twice daily. Because HCN channels are also expressed in the retina (where they are involved in the response to abrupt changes in luminosity), ivabradine produces a characteristic visual side effect known as phosphenes — transient flashes or enhanced brightness in the visual field, especially during sudden light changes.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~1 h fasting; food delays absorption by ~1 h. Absolute oral bioavailability ~40% (extensive first-pass in gut and liver). Food increases plasma exposure by 20–40% and reduces variability | Always administer with food. Inter-patient variability is meaningful — titrate to clinical response (HR), not to a fixed dose. |
| Distribution | Vd at steady state ~100 L; plasma protein binding ~70% (mainly albumin) | Routine drug-displacement interactions are not clinically significant. |
| Metabolism | Extensive hepatic and intestinal metabolism via CYP3A4 (sole pathway). PK linear over 0.5–24 mg. Active N-desmethyl metabolite (S 18982) is equipotent and circulates at ~40% of parent concentrations; also CYP3A4-cleared | CYP3A4 inhibitors and inducers dominate the interaction profile. Strong CYP3A4 inhibitors are contraindicated; moderate CYP3A4 inhibitors and inducers should be avoided. |
| Elimination | Total clearance ~24 L/h; renal clearance ~4.2 L/h. Approximately 4% excreted unchanged in urine; metabolites cleared roughly equally via faeces and urine. Distribution t½ ~2 h; effective t½ ~6 h | Renal impairment has minimal effect on exposure unless severe (CrCl <15 mL/min, where data are absent). Hepatic impairment is the more important PK consideration. |
Side Effects
The adverse-effect profile is dominated by predictable on-target effects: bradycardia, atrial fibrillation, and phosphenes. The Corlanor PI reports incidences in two complementary ways: absolute rates over the SHIFT trial median exposure of 21.5 months (n=3,260 ivabradine vs n=3,278 placebo), and rates per patient-year for the principal safety signals. Both are presented below.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Bradycardia (SHIFT, absolute rate over 21.5 months) | 10.0% vs 2.2% placebo | Per Corlanor PI Table 2. The same trial reports a per-patient-year rate of 6.0% (2.7% symptomatic + 3.4% asymptomatic) versus 1.3% placebo. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypertension / increased blood pressure | 8.9% vs 7.8% placebo | Modest excess over placebo. Listed in PI Table 2; usually managed with adjustment of background antihypertensive therapy. |
| Atrial fibrillation | 8.3% vs 6.6% placebo | Per PI Table 2. The PI separately reports a per-patient-year rate of 5.0% (ivabradine) versus 3.9% (placebo). Discontinue ivabradine if AF develops. |
| Phosphenes / luminous visual phenomena | 2.8% vs 0.5% placebo | Transient enhanced brightness, halos, kaleidoscopic effects — usually triggered by abrupt luminosity change. Mediated by retinal HCN inhibition (per PI Section 12.1). Onset within the first 2 months; usually mild–moderate; led to discontinuation in <1%. |
Note: Additional adverse reactions in the current Corlanor PI are listed only as adverse-event categories rather than discrete percentages. Postmarketing reports include syncope, hypotension, torsade de pointes, ventricular tachycardia, ventricular fibrillation, angioedema, erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment (frequencies unknown).
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Symptomatic bradycardia | 2.7% per patient-year (SHIFT) vs <1% placebo | First 2–3 months | Reduce dose by 2.5 mg BID; if at 2.5 mg BID, discontinue. Severe bradycardia: atropine, isoproterenol; temporary pacing if refractory. |
| New-onset atrial fibrillation | 5.0% per patient-year (SHIFT) | Any time during therapy | Discontinue ivabradine if AF develops (per PI Section 5.2); manage rhythm/rate per AF guidelines. |
| Pediatric bradycardia (asymptomatic / symptomatic) | 6.8% / 4.1% (vs 2.4% / 0% placebo) | During titration | Per PI: managed by dose titration without leading to study discontinuation. Consider 0.02 mg/kg BID if bradycardia at recommended initial dose. |
| Torsades de pointes / ventricular tachycardia / ventricular fibrillation | Postmarketing — frequency unknown | Any time, often with concomitant QT-prolonging drugs | Avoid concomitant QT-prolonging agents; correct electrolytes; discontinue ivabradine. |
| Syncope / hypotension | Postmarketing | Any time | Hold dose; check HR and BP; reassess concomitant chronotropic and antihypertensive therapy. |
| Angioedema, urticaria, severe rash | Postmarketing — rare | Any time | Discontinue immediately; standard hypersensitivity management. |
| Fetal toxicity (animal data) | Embryo-fetal toxicity and cardiac teratogenicity at 1–3× human exposure in rats | First trimester | Avoid in pregnancy unless benefit clearly outweighs risk; ensure effective contraception in patients of reproductive potential. |
There is no specific antidote for ivabradine. Per the Corlanor PI Section 10, overdose may cause severe and prolonged bradycardia. Management is supportive: temporary cardiac pacing for poor haemodynamic tolerance, IV fluids, atropine, and IV beta-stimulating agents such as isoproterenol. Monitor for QT prolongation and torsades de pointes.
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Bradycardia (symptomatic or severe) | Most common drug-specific cause | ~3% had withdrawn for bradycardia at 1 month in SHIFT. |
| New atrial fibrillation | Variable | PI mandates discontinuation if AF develops; rate not separately tabulated. |
| Phosphenes / visual disturbance | <1% (per PI) | Most patients tolerate; symptoms often resolve during continued treatment. |
| Other AEs (rash, hypotension, etc.) | Uncommon | Heterogeneous and individually rare. |
New-onset AF is the single most clinically important adverse event of ivabradine. Per Section 5.2 of the Corlanor PI, cardiac rhythm should be regularly monitored and ivabradine discontinued if atrial fibrillation develops. Patients should be counselled at every visit to report palpitations, an irregular pulse, chest pressure, or worsened breathlessness. Continuing ivabradine after persistent AF develops exposes the patient to risk without therapeutic benefit, since the drug is ineffective outside sinus rhythm.
Drug Interactions
Ivabradine is metabolised exclusively by CYP3A4. The interaction profile is therefore dominated by CYP3A4 inhibitors (which raise levels and amplify bradycardia) and inducers (which lower levels and reduce efficacy). Pharmacodynamic interactions with other negative chronotropes are also clinically important. Strong CYP3A4 inhibitors are absolutely contraindicated with ivabradine per the Corlanor PI.
Monitoring
Monitoring centres on heart rate (the therapeutic and toxicity endpoint) and rhythm (to detect new atrial fibrillation, the principal class effect). Routine biochemistry and ECG are needed at baseline and at each titration step.
-
Resting heart rate
Baseline; 2 weeks after start; 2 weeks after each dose change; every clinic visit thereafter
Routine Adult target 50–60 bpm. Pediatric target ≥20% HR reduction. Reduce dose if <50 bpm or symptomatic bradycardia; discontinue if <50 bpm despite minimum dose. Adult indication requires baseline HR ≥70 bpm. -
Cardiac rhythm (palpitation history, ECG when triggered)
Baseline; with new symptoms or irregular pulse
Routine Per PI Section 5.2: regularly monitor cardiac rhythm. Discontinue Corlanor if atrial fibrillation develops. Counsel patients to report palpitations or irregular heartbeat. -
12-lead ECG
Baseline; with new symptoms, dose change, or interacting drugs
Routine Confirm sinus rhythm before initiation. Look for AV block, bundle branch block, sinus pauses. Per PI: 2nd-degree AV block is a precaution; 3rd-degree AV block without pacemaker is a contraindication. -
Blood pressure
Baseline; periodically
Routine Per PI Section 4: clinically significant hypotension is a contraindication. Modest BP elevation (~1% excess vs placebo) reported in SHIFT. -
Liver function tests
Baseline; periodically
Routine Severe hepatic impairment (Child-Pugh C) is a contraindication; mild–moderate impairment requires no formal dose adjustment but warrants closer clinical observation. -
Electrolytes (K, Mg)
Baseline; with diuretic changes; periodically
Routine Important if concomitant QT-prolonging drugs; correct any abnormality before continuing therapy. -
Visual symptoms
Every visit; especially in first 2 months
Trigger-based Phosphenes are usually mild and transient. Counsel about caution while driving in changing light. Persistent or severe symptoms warrant ophthalmologic referral. -
Pregnancy status (women of reproductive potential)
Baseline and periodically
Trigger-based Per Corlanor PI Section 8.1 and 8.3: animal studies show fetal toxicity and teratogenicity. Confirm effective contraception is in place; counsel before initiation.
Contraindications & Cautions
Absolute Contraindications (Corlanor PI Section 4)
- Acute decompensated heart failure.
- Clinically significant hypotension.
- Sick sinus syndrome, sinoatrial block, or third-degree AV block — unless a functioning demand pacemaker is present.
- Clinically significant bradycardia.
- Severe hepatic impairment (Child-Pugh C).
- Pacemaker dependence (heart rate maintained exclusively by the pacemaker).
- Concomitant use of strong CYP3A4 inhibitors — examples per PI: azole antifungals (e.g., itraconazole), macrolide antibiotics (clarithromycin, telithromycin), HIV protease inhibitors (e.g., nelfinavir), and nefazodone.
Warnings & Precautions — Specialist Input or Caution
- Atrial fibrillation (PI 5.2) — ivabradine increases the risk; discontinue if AF develops.
- Bradycardia and conduction disturbances (PI 5.3) — risk increased by sinus node dysfunction, 1st- or 2nd-degree AV block, bundle branch block, ventricular dyssynchrony, and concomitant negative chronotropes (digoxin, diltiazem, verapamil, amiodarone).
- Second-degree AV block — not recommended unless a functioning demand pacemaker is present.
- Concomitant heart-rate-lowering calcium channel blockers (verapamil, diltiazem) — avoid combination per US PI; contraindicated per EU SmPC.
- Demand pacemakers set ≥60 bpm — Corlanor not recommended (cannot achieve target HR <60 bpm).
- Pregnancy (PI 5.1, 8.1) — fetal toxicity demonstrated in animal studies. Effective contraception is required during therapy and patients should be counselled before starting.
- Lactation (PI 8.2) — breastfeeding not recommended (animal data show transfer to milk).
- Severe renal impairment (CrCl <15 mL/min) — no data available; use with caution.
- Mild–moderate hepatic impairment (PI 8.6) — no formal dose adjustment; PK similar to normal hepatic function.
- Older adults / vulnerable patients — start at 2.5 mg twice daily.
Ivabradine does not carry a boxed warning. The Corlanor PI’s three principal Warnings and Precautions are: (1) fetal toxicity — based on animal teratogenicity at clinically relevant exposures, with cardiac malformations and complex anomalies of major arteries; effective contraception is required for patients of reproductive potential; (2) atrial fibrillation — patients should be regularly monitored and ivabradine discontinued if AF develops; and (3) bradycardia and conduction disturbances — risk is heightened by sinus node disease, AV block, bundle branch block, concomitant negative chronotropes, and CYP3A4 inhibitors.
Strong CYP3A4 inhibitors are absolutely contraindicated; concomitant heart-rate-lowering calcium channel blockers (diltiazem, verapamil) should be avoided per US PI (and are contraindicated per EU SmPC) because they both elevate ivabradine exposure and add to its bradycardic effect.
Patient Counselling
Purpose of Therapy
Ivabradine slows the heart rate without affecting how strongly the heart pumps. In heart failure, a slower heart rate gives the heart more time to fill between beats and reduces overall workload, lowering the chance of admission to hospital for worsening symptoms. Patients should understand that ivabradine is added to — not a replacement for — their other heart-failure medications. The drugs that improve survival (ACE inhibitors, ARNIs, beta-blockers, MRAs, and SGLT2 inhibitors) should not be reduced or stopped because of ivabradine.
How to Take
Take ivabradine twice a day, with food (for example with breakfast and dinner). Avoid grapefruit and grapefruit juice and St. John’s wort during therapy. If a dose is missed, do not take a replacement dose — take the next dose at the usual time. Do not stop ivabradine suddenly without speaking to the prescriber. The dose is adjusted according to the resting pulse measured in clinic; some patients find it useful to keep a simple log of their pulse and any new symptoms between visits.
Sources
- CORLANOR (ivabradine) tablets and oral solution — full prescribing information. Amgen Inc., revised April 2019 (Reference ID: 4422121). FDA label PDF Most current US label including pediatric dosing approved in 2019; primary source for indications, dosing, contraindications, adverse-event data, and pharmacokinetics used throughout this monograph.
- CORLANOR (ivabradine) original FDA approval label (April 2015). FDA approval document Original adult approval — source for SHIFT trial adverse-event tabulation reproduced in current PI.
- PROCORALAN (ivabradine) — Summary of Product Characteristics. European Medicines Agency. EMA SmPC European labelling — includes the chronic stable angina indication that is not approved in the US, and additional pooled safety data including the contraindication for verapamil/diltiazem combination.
- Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875–885. doi:10.1016/S0140-6736(10)61198-1 Pivotal RCT (n=6,558 randomised) supporting the adult HFrEF indication; reduction in composite of cardiovascular death or HF hospitalisation, driven by HF hospitalisation (HR 0.82, 95% CI 0.75–0.90).
- Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807–816. doi:10.1016/S0140-6736(08)61170-8 Trial in CAD with LV systolic dysfunction; no benefit on primary composite (HR 1.00) but suggested heart-rate-related benefit in HR ≥70 bpm subgroup, informing SHIFT design.
- Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure (SIGNIFY). N Engl J Med. 2014;371(12):1091–1099. doi:10.1056/NEJMoa1406430 Negative trial in CAD without HF (HR 1.08); higher discontinuation rate than SHIFT and confirmation of AF risk.
- Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEF. Ivabradine in Children With Dilated Cardiomyopathy and Symptomatic Chronic Heart Failure. J Am Coll Cardiol. 2017;70(10):1262–1272. doi:10.1016/j.jacc.2017.07.725 Pediatric pivotal trial (n=116, 2:1 randomisation) supporting the 2019 FDA approval for children ≥6 months with HF due to dilated cardiomyopathy.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263–e421. doi:10.1016/j.jacc.2021.12.012 Current US heart-failure guideline — gives ivabradine a Class 2a, Level B-R recommendation in symptomatic chronic stable HFrEF (LVEF ≤35%, sinus rhythm, HR ≥70 bpm, on max-tolerated beta-blocker).
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. doi:10.1093/eurheartj/ehab368 European HF guideline — Class IIa recommendation for ivabradine in symptomatic HFrEF with sinus rhythm and HR ≥70 bpm despite GDMT.
- Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029 Reference document for off-label use in inappropriate sinus tachycardia and POTS.
- Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2024;83(15):1444–1488. doi:10.1016/j.jacc.2023.12.024 Updated ACC consensus pathway — situates ivabradine within current GDMT framework and reaffirms the SHIFT-population eligibility criteria.
- DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757–1765. doi:10.2165/00003495-200464160-00003 Foundational reference on the molecular basis of If current inhibition and HCN channel pharmacology.
- Psotka MA, Teerlink JR. Ivabradine: Role in the Chronic Heart Failure Armamentarium. Circulation. 2016;133(22):2066–2075. doi:10.1161/CIRCULATIONAHA.115.018094 Comprehensive review synthesising SHIFT, BEAUTIFUL, and SIGNIFY data, including discontinuation comparisons and AF risk meta-analyses.
- Martin RIR, Pogoryelova O, Koref MS, Bourke JP, Teare MD, Keavney BD. Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. Heart. 2014;100(19):1506–1510. doi:10.1136/heartjnl-2014-305482 Meta-analysis confirming AF risk is meaningfully higher than originally reported in product labelling.
- Tanboga IH, Topcu S, Aksakal E, et al. The Risk of Atrial Fibrillation With Ivabradine Treatment: A Meta-analysis With Trial Sequential Analysis of More Than 40000 Patients. Clin Cardiol. 2016;39(10):615–620. doi:10.1002/clc.22578 Larger meta-analysis (n >40,000) confirming an approximately 24% relative risk increase in AF with ivabradine.