inappropriate sinus tachycardia: focus on ivabradine · inappropriate sinus tachycardia is defined...

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eInappropriate Sinus Tachycardia: Focus on Ivabradine

Hany S. Abed, MBBS PhD†; Jordan Fulcher, MBBS†; Michael J Kilborn, MBBS PhD†;

Anthony C. Keech, MBBS, MClinEpi.†

†Department of Cardiology, Royal Prince Alfred Hospital and NHMRC Clinical Trials Centre,

University of Sydney, Sydney, NSW, Australia

Address for correspondence:

Professor Anthony C. Keech

NHMRC Clinical Trials Centre

K25 - Medical Foundation Building

University of Sydney, NSW, Australia, 2006

Phone: +61 9562 5003

Fax: +61 9565 1863

Email: [email protected]

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/imj.13093

This article is protected by copyright. All rights reserved.

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eAbstract

Inappropriate sinus tachycardia (IST) is an incompletely understood condition characterised

by an elevation in heart rate (HR) accompanied by wide ranging symptoms, in the absence

of an underlying physiological stimulus. The condition often takes a chronic course with

significant adverse effects on quality of life. Currently there is no effective treatment for IST.

Beta-blockers, generally considered the cornerstone of treatment, are often ineffective and

poorly tolerated. Ivabradine is a novel sinus node If “funny current” inhibitor which reduces

the HR. It has been approved for the treatment of beta-blocker refractory chronic systolic

heart failure and chronic stable angina, but more recently shown promise in the treatment

of IST. This review provides an overview of IST prevalence and mechanisms, followed by an

examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.

Keywords: Inappropriate sinus tachycardia; Ivabradine


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eIntroduction

Inappropriate sinus tachycardia is defined as a persistent non-paroxysmal elevation in the

resting and exertional HR with no identifiable physiological or pathological stimulus(1).

There is no formally accepted HR threshold for the definition of IST. This is, in part, related

to the wide range of normal HR variation within the population, its dependency on age(2)

and underlying physiological status. Population studies show that, in addition to an inverse

correlation with age, mean intrinsic HR (HR under complete pharmacologic autonomic

blockade or autonomic denervation) is independently associated with levels of physical

activity, blood pressure, tobacco smoking, intake of caffeine and body height(3). The 2015

Heart Rhythm Society expert consensus statement defines IST as a “sinus heart rate

>100bpm at rest (with a mean 24-hour heart rate >90 bpm not due to primary causes) and

associated distressing symptoms of palpitations”(1, 4, 5). Other commonly described

symptoms include dizziness, light headedness, dyspnoea and pre-syncope.

Prevalence and Clinical Course of IST

An Icelandic study of randomly sampled patients from insurance registries for hypertension

reimbursement, described the prevalence and course of IST using the above definition(4).

The largest of its kind, the study rigorously excluded differential diagnoses and mimics of

the condition. However, the overall population was relatively small (604) and 149 subjects

were on beta adrenoceptor antagonists for hypertension treatment. Of the 604 patient

cohort, 7 fulfilled the definition for IST, yielding a prevalence of 1.16%. This is greater than

the estimates for Wolff-Parkinson-White syndrome (0.15-0.31%)(6). No differences were


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efound between IST and control patients with regards to age, gender, smoking habits, alcohol

intake, physical activity levels and adiposity. The mean age and 24-h ambulatory systolic

pressure in the IST group was 47±7 years and 147±11 mmHg, respectively, noting the likely

bias related to the cohort source (systemic arterial hypertension). After a mean follow-up of

6.0±2.4 years, the outlook for the condition was found to be benign, particularly for the

development of tachycardia-mediated cardiomyopathy and survival. However, at follow-up,

there was persistence of symptoms, elevated resting HR and elevated average daily HR.

Mechanisms in IST

The trigger and mechanism for the tachycardia in IST is unknown. Expert anecdotal evidence

has suggested halogenated hydrocarbon exposure as one possible cause, although this is

unsubstantiated(7). Peripheral and central neurohormonal mediators of autonomic control

or their receptors have been implicated, however this remains speculative(8, 9). Notably, an

exaggerated HR response to isoprenaline infusion occurs in less than one third of

patients(10). This observation and the relative inefficacy of beta-blockade have led some

investigators to believe that the condition may represent a sinus node channelopathy rather

than an abnormality of autonomic modulation(11). Some clinical studies have pointed

towards an elevation in intrinsic HR mediated by ATP sensitive potassium channels in sinus

node tissue(12). A small study has identified greater plasma levels of beta adrenoceptor

antibodies in patients with IST as compared to controls(11). The presence of these

antibodies has been hypothesised to result in receptor activation function and second

messenger mediated calcium influx and depolarisation. As yet there have been no reports

of specific genetic abnormalities associated with IST.


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e

Clinical Presentation and Diagnosis

Inappropriate sinus tachycardia often presents non-specifically with symptoms including

pre-syncope, syncope, dyspnoea, exercise intolerance, dizziness, light-headedness,

weakness and palpitations either chronically or in a relapsing and remitting pattern. Their

severity may vary from mild to significantly disabling, and importantly may not parallel the

severity of the tachycardia.

Essential to the diagnosis of IST is exclusion of underlying causes for an appropriate sinus

tachycardia such as anaemia, cardiac failure, infection, stimulant intake, thyrotoxicosis,

anxiety or psychosis. Therefore, in addition to undertaking a thorough general medical

assessment, laboratory (serum thyrotropin levels and full blood count) tests, a 12-lead ECG

and ambulatory cardiac rhythm monitors are required. The latter may be in the form of 24-

hour, 48-hour, 7-day or longer ambulatory monitors which may reveal occult arrhythmias or

allude to non-physiological phenomena such as lack of nocturnal vagal predominance. In

accordance with expert consensus, the clinical diagnosis is made, after exclusion of

differentials, in symptomatic patients with a persisting daytime sinus tachycardia

Differential Diagnosis

Certain cardiac supraventricular tachycardias (SVT), which are amenable to curative

treatment, may present with similar symptoms to IST. Electrocardiographic examples are

shown in Figure 1 [Figure 1]. Accessory pathway mediated SVT and atrioventricular nodal

re-entry tachycardia (AVNRT) almost always have a sudden onset and offset. The 12-lead


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eECG in AVNRT is usually normal at baseline and subtle retrograde conducted P-waves are

often seen during SVT. Accessory pathways may result in typical delta waves and short PR

duration at baseline if conducting in the anterograde direction, and therefore it is manifest.

Generally, if the accessory pathway conducts in the retrograde direction, features of pre-

excitation are absent at baseline, and therefore it is concealed. Accessory pathway

mediated SVT may be broad or narrow QRS complex, depending on the directionality of

pathway conduction during SVT. One important pre-excitation syndrome mostly affecting

children and teenagers is the permanent form of reciprocating junctional tachycardia (PJRT).

This incessant form of long RP SVT commonly utilises an accessory pathway which is located

in the right inferior paraseptal region and is often drug refractory. Its chronic nature and

tachycardia rates as low as 130bpm may mask the diagnosis for months and subsequently

promote a tachycardia-mediated cardiomyopathy. The latter is reversible after accessory

pathway ablation(13) (14).

Atrial tachycardia (AT) on the other hand may oftentimes be difficult to differentiate from

IST, particularly when arising from areas adjacent to the sinus node, such as superior crista

terminalis or even within the sinus node in the form of re-entry. Although 12-lead ECG P

wave axis and morphology will often provide vital clues to the AT site of origin, an AT focus

close to the sinus node will generate a P wave morphology very similar or identical to that of

sinus rhythm. The onset of tachycardia and symptoms, in addition to other clinical features,

may point to either IST or AT.

Another condition to consider is Postural Orthostatic Tachycardia Syndrome (POTS), as both

POTS and IST have overlapping clinical features. This increasingly recognised disorder is a

condition of autonomic dysfunction characterised by a hyperadrenergic response to


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eorthostatic change in posture, with symptoms of dizziness, pre-syncope and diaphoresis

(15). An exaggerated HR response to isoprenaline may be seen in both IST and POTS, and

therefore a detailed clinical assessment is required to demonstrate the orthostatic

relationship to symptoms and HR changes which occur in POTS. A head up tilt table test may

be useful in demonstrating a 30 bpm HR rise (or tachycardia >120 bpm) on assuming the

upright position from being supine. In the supine position, the 12-lead ECG in POTS patients

is rarely >100 bpm whereas in IST the resting HR is often >100 bpm.

Conventional Management Strategies for IST

The use of negative chronotropic agents such as beta-blockers and calcium antagonists is

often unsuccessful in controlling IST symptoms and HR(16). Intolerance to beta-blockade

side effects may be particularly troublesome in this patient group. Clinicians have

occasionally trialled beta adrenoceptor antagonists with intrinsic sympathetic activity (for

example, pindolol or acebutolol). The goal with this approach is to supress elevated HR

whilst minimising anti-adrenergic related adverse effects. However, there is no evidence

supporting an advantage for beta-blockers with intrinsic sympathetic activity over pure

beta-blockers. There is an identified overlap of IST in some instances with anxiety disorders,

which may also require specific treatment(1).

Invasive techniques are reserved for patients highly debilitated by drug-refractory

symptoms. Limited experience exists for surgical or radiofrequency catheter modification of

the sinus node zone in these patients. The effectiveness of catheter ablation in IST is at best

modest. At an experienced centre, after a mean follow-up of 4 months, symptoms recurred


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ein 27% of patients deemed to have acute procedural success(17). Long term symptom

control was not achieved in one third of patients despite repeat procedures. The risk of

complications is low but not non-trivial. Sinus node dysfunction requiring permanent pacing,

right phrenic nerve injury and superior vena cava syndrome are uncommon but serious

complications.

The ablate and pace strategy is often undesirable in view of the sacrifice of atrio-ventricular

conduction and complete reliance on permanent pacing in this younger demographic.

Ivabradine

Overview of Ivabradine

Ivabradine is a novel selective inhibitor of cardiac ionic channels which results in negative

chronotropic effects through a reduced sinoatrial depolarisation rate, with negligible effects

on contractility. The agent has been approved in Australia since 2006 primarily as a second

line agent for patients with chronic stable angina who are intolerant of, or have a

contraindication to beta-blockers, or as add-on therapy to beta-blockers in patients with

inadequately controlled HR. The drug has been studied for its quantitative impact on

exercise tolerance in patients with coronary artery disease and for its role in the treatment

of chronic systolic (impaired ejection fraction) heart failure(18-23). Currently, Ivabradine is

only covered by the Pharmaceutical Benefit Scheme (PBS) for its use in Heart failure and

although approved for use in angina, this is currently only as a private prescription. In

addition, emerging evidence has shown ivabradine to be of potentially significant benefit in

patients with IST(24-26).


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ePharmacology of Ivabradine

Sinoatrial nodal cells have an innate automaticity involving a slow inward current of sodium

(and calcium), coupled with a slowly diminishing outward potassium current. This results in

a cyclical drift of the resting membrane potential towards depolarization threshold, and is

known as the pacemaker or “funny” current (If) [Figure 2]. It was dubbed “funny” because of

its unique characteristics when compared to other cardiac membrane channels. The If

current is mostly generated through a non-selective voltage gated transmembrane cation

channel known as the Hyperpolarization-activated cyclic nucleotide gated (HCN4) channel,

which is strongly expressed in the sinus node region. Ivabradine is a chiral molecule with

only the S-enantiomer showing voltage-dependent affinity to the HCN4/If channel. Accessing

the intracellular aspect of the channel, the drug blocks the transmembrane channel pore,

selectively inhibiting inward cation movement. This slows the rate of pacemaker

depolarization and thereby reduces sinus node beating rate with no appreciable effects on

myocardial repolarisation or contractility. Ivabradine does not affect the QT interval on the

surface electrocardiogram (ECG). In addition to a neutral effect on myocardial inotropy, no

measurable changes are observed in systemic vascular resistance, cardiac output or

coronary perfusion pressure. At therapeutic doses (5-7.5 mg twice daily oral dosing), resting

and exertional HR are reduced by approximately 10 bpm, with a ceiling effect at doses of 20

mg twice daily. In the absence of food, an oral dose has only about 40% bioavailability due

to extensive first pass hepatic metabolism by cytochrome P450 (CYP) 3A4. Potent CYP3A4

inhibitors such as macrolide antibiotics, azole antifungals and protease inhibitors may

increase plasma levels. Additionally, concomitant use of moderately potent CYP3A4

inhibitors such as diltiazem and verapamil may result in a combined pharmacokinetic


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e(increased serum Ivabradine) and pharmacodynamic (potentiation of bradycardia effect)

interaction.

Ivabradine is a weak inhibitor of CYP3A4 and is therefore unlikely to influence metabolism of

other drugs, or their plasma levels. Food delays absorption but increases peak plasma levels

and overall bioavailability to 70%. Trough plasma levels occur 12 hours after the last dose

and on that basis, clinical studies into its quantitative effect on exercise tolerance are

performed at this nadir state.

Contra-indications and adverse reactions

Ivabradine is generally contraindicated in the presence of resting bradycardia (<60 bpm),

hypotension, and in sinus node dysfunction. Atrioventricular (AV) nodal disease is a relative

contraindication however the drug may be used with caution in first and second degree AV

block. Due to the lack of clinical studies into its safety or efficacy in atrial or ventricular

tachyarrhythmias, Ivabradine should generally be avoided in those conditions. Finally, in

conditions that predispose to an acquired long QT interval, Ivabradine should be avoided or

used with careful monitoring to prevent excessive bradycardia and exacerbation of the

polymorphic ventricular tachycardia risk.

Ivabradine is shown to be well tolerated, with dose-dependent predictable adverse

reactions. The most common cardiovascular adverse reactions are bradycardia and

hypotension whereas visual disturbances are the most common non-cardiovascular effects.

Bradycardia (<60 bpm) was estimated at 4.2% in a randomised clinical study(31). This is

comparable to but somewhat lower than the prevalence of bradycardia noted for the beta

adrenoceptor antagonist, atenolol (5.8%). The combination of beta-blocker and Ivabradine


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euse results in an additive risk of bradycardia, with the SIGNIFY study showing a prevalence

of 17.9% in a randomised double-blind multi-centre clinical trial setting(19). The most

common adverse reaction overall is a phenomenon of visual phosphenes (14.5%)(27). This

consists of bright illuminations at the periphery of the visual field exacerbated by sudden

changes in the ambient level of brightness. This peculiar effect appears to be benign with

the vast majority of patients reporting a mild to moderate level of intensity. The condition is

self-resolving in >75% of patients within a matter of months without dose modification or

treatment interruption(27). Less than 1% of patients reported having to stop treatment or

modification of their daily activities to accommodate for this visual disturbance.

Role of Ivabradine in IST

With the development of ivabradine and insights into its pharmacologic mechanisms, some

experimental use in IST has emerged(25). Early pilot work demonstrated the effectiveness of

Ivabradine in reducing minimum, mean and maximum HR in addition to symptom

improvement or complete resolution(27). In addition, the drug appeared to be well

tolerated.

Several non-randomised open label studies of short to intermediate follow-up duration

showed scope for the efficacy and tolerability of Ivabradine in IST. In 2010, an open label

efficacy study in 18 subjects showed the drug to be well tolerated and associated with a

significant reduction in maximal and median HR as well as greater workloads achieved on

standard treadmill stress testing. One patient was excluded from the study due to persistent

phosphene visual effects despite dosage reduction(23).


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eIn 2012 a small randomised and placebo controlled cross-over study compared Ivabradine

to placebo in 21 patients with IST(28). After 6 weeks of therapy, patients taking Ivabradine

(either 5 mg or 7.5 mg twice daily) experienced a 12 bpm reduction in resting HR, 18 bpm

reduction on exercise, 16 bpm reduction on standing and 11 bpm reduction in mean 24

hour HR. These statistically significant improvements were associated with improved

exercise tolerance and a quantitative reduction in symptom severity of >70%. Overall, more

than 45% reported complete resolution of symptoms. In 2013, a study comparing long

acting metoprolol (succinate) to Ivabradine in 20 patients was performed assessing changes

in HR and quantitative symptomatology(16). Patients who had IST refractory to traditional

beta-blockers were switched from metoprolol succinate to Ivabradine after 4 weeks of

therapy. Although mean 24 hour HR reduction was similar between both agents, Ivabradine

showed a greater reduction in daytime HR reduction. The metoprolol group experienced

significantly greater troublesome bradycardia and hypotension requiring dosage reduction.

Using an IST specific symptomatology scoring algorithm, Ivabradine treatment showed

superior symptom attenuation as compared with metoprolol succinate.

An open label study of longer duration in 2013 showed favourable results and in addition,

cessation of the drug after 1 year of therapy was associated with maintained HR benefits in

80% of patients(29). The latter observation points towards a possible mechanism beyond

symptom suppression only but may represent prevention of the disease progression

through favourable functional and/or structural cardiac remodelling.

The Ivabradine Versus Beta-blockers in the Treatment of Inappropriate Sinus Tachycardia

(CIBIST; Clinical Trials Identifier NCT01657136) is an open label non-randomised study


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ecomparing Ivabradine to the long half-life beta-blocker, bisoprolol. The phase III study

primary outcome of HR reduction is expected to be released in 2016.

Table 1 shows key findings of several important studies of different IST management

modalities.

Guideline Recommendations for IST Management

The last focused ACC/AHA/ESC supraventricular arrhythmia guidelines in 2003 provided a

class I recommendation for beta blockers, class IIa for calcium channel blockers and class IIb

for catheter ablation, noting that all three treatments had level C evidence(30). However in

2015 the Heart Rhythm Society (HRS) expert consensus statement assigned a Class IIa

recommendation for the use of ivabradine with level B-R evidence (moderate randomised

trial) and removed recommendations for other pharmacotherapies. In addition, catheter

ablation was actively recommended against with level E (consensus) evidence(5).

Cost Implications if Ivabradine was subsidised for use in IST

Inappropriate sinus tachycardia is an uncommon condition. Epidemiological estimates from

Still et al put the prevalence at 1.16% with preponderance in middle aged adults (mean age

47±7 years)(4). Based on this and the comparative study between Ivabradine and

Metropolol succinate, we provide a crude estimate of cumulative costs incurred for funding

of Ivabradine by the PBS. The PBS is a program of the Australian Government that provides

subsidised prescription drugs to residents of Australia. Of the 15.9 million Australians aged

15-65 years of age (Australian Bureau of Statistics, 2010), 184,440 individuals could feasibly

satisfy conventional diagnostic criteria for IST. Based on comparative data from Ptaszynski

et al(16), we posit that considering a worst case scenario, 50% of patients being treated for


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eIST could require step-up therapy from either beta-blockade or calcium antagonists to

Ivabradine. The Food and Drug Administration of the United States recently approved

Ivabradine for patients who have symptoms of heart failure that are stable with a resting HR

of at least 70 beats per minute and are also taking beta-blockers at the highest dose they

can tolerate. The European Medicines Agency had set the cut-off HR at 75 beats per minute

for the same indication. In Australia, Ivabradine is approved for use in refractory chronic

stable angina and chronic systolic heart failure. Current PBS subsidy indications for

Ivabradine are for NYHA class II or III systolic heart failure (LVEF < 35%) in sinus rhythm, with

a HR ≥77 beats per minute, despite maximum tolerated beta-blocker dosage. Economic

recommendations submitted by Servier Laboratories Australia Pty Ltd to the PBS Advisory

Committee (July 2012) for funding of Ivabradine for systolic heart failure, estimated a net

cost to the government at $10-30 million by 5 years of listing. The incremental cost

effectiveness ratio (ICER) expressed as a cost/quality adjusted Life Year (cost/QALY) is

conservatively estimated at 65% for Ivabradine. In 2007-08, the prevalence of ischaemic

heart disease and cardiac failure were 685,000 (Australian Institute of Health and Welfare

[AIHW], 2012) and 276,250 (AIHW, 2011) respectively. Therefore, the $10-30 million 5 year

cost for funding Ivabradine for the 961,250 patients with ischemic heart disease or cardiac

failure may be used to model the anticipated costs for funding Ivabradine for the estimated

92,220 symptomatic patients with IST refractory to currently used pharmacotherapy (beta

blockers and calcium channel antagonists). This 5 year estimate would be $1-2.9 million. It

should be emphasized that the availability of Ivabradine as a potentially efficacious

treatment option for IST would likely negate the need for invasive radiofrequency catheter

modification of the sinus node, subsequently offsetting invasive treatment costs in patients

with refractory symptoms. Moreover, in our experience, efficacious treatment in this


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eyounger patient population can reduce indirect economic costs associated with the number

of sick days, unemployment and disability claims.

Conclusion

Inappropriate sinus tachycardia is a condition with a best estimate prevalence of 1.16% in

the general adult population. The condition has a wide spectrum of symptom severity and

due to its predilection in the young, it has the potential to adversely impact daily activities,

particularly effort tolerance and personal economic productivity, despite its overall benign

course. Whilst it remains ill-defined on a cellular level, it appears that IST is probably a sinus

node channelopathy in origin rather than a disease of altered autonomic modulation (as

opposed to POTS, an important differential diagnosis). The mainstay of therapy has been

beta-blockers. Despite some effect at reducing HR, these agents appear to have limited

benefit and a significant adverse effect profile in this active younger group of patients.

Catheter ablation remains an evolving technique with modest results despite multiple

procedures. In small clinical studies, Ivabradine has shown benefit in HR reduction,

quantitative improvement in exercise capacity and subjective symptom burden

amelioration. The drug is well tolerated and appears to carry a lower proarrhythmia risk. For

a chronic condition often becoming clinically problematic in management, Ivabradine shows

much promise as a potential therapy of choice for beta-blocker intolerant or sub-optimally

responsive patients. Currently there are no large prospective randomised double-blinded

placebo controlled studies examining the efficacy of the various treatment modalities.

However the updated Heart Rhythm Society guidelines recommending Ivabradine with Class

IIa, Level B-R evidence, reflects the progressively accruing evidence base for its use above all


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eother conventional treatment options. Given the low prevalence of IST and evidence for

significant physiological and functional improvement with ivabradine, when considering

suitability for prescription subsidy, ivabradine may well represent a cost-effective and

relatively inexpensive treatment option.

References

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e16. Ptaszynski P, Kaczmarek K, Ruta J, Klingenheben T, Wranicz JK. Metoprolol succinate vs. ivabradine in the treatment of inappropriate sinus tachycardia in patients unresponsive to previous pharmacological therapy. Europace. 2013 Jan;15(1):116-21. 17. Man KC, Knight B, Tse HF, Pelosi F, Michaud GF, Flemming M, et al. Radiofrequency catheter ablation of inappropriate sinus tachycardia guided by activation mapping. J Am Coll Cardiol. 2000 Feb;35(2):451-7. 18. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013 Oct;166(4):654-61 e6. 19. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875-85. 20. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. 2010 Jan;12(1):75-81. 21. Fox K, Komajda M, Ford I, Robertson M, Bohm M, Borer JS, et al. Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur Heart J. 2013 Aug;34(29):2263-70. 22. Ferrari R, Ford I, Fox K, Steg PG, Tendera M. The BEAUTIFUL study: randomized trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction - baseline characteristics of the study population. Cardiology. 2008;110(4):271-82. 23. Calo L, Rebecchi M, Sette A, Martino A, de Ruvo E, Sciarra L, et al. Efficacy of ivabradine administration in patients affected by inappropriate sinus tachycardia. Heart Rhythm. 2010 Sep;7(9):1318-23. 24. Zellerhoff S, Hinterseer M, Felix Krull B, Schulze-Bahr E, Fabritz L, Breithardt G, et al. Ivabradine in patients with inappropriate sinus tachycardia. Naunyn Schmiedebergs Arch Pharmacol. 2010 Dec;382(5-6):483-6. 25. Kaplinsky E, Comes FP, Urondo LS, Ayma FP. Efficacy of ivabradine in four patients with inappropriate sinus tachycardia: a three month-long experience based on electrocardiographic, Holter monitoring, exercise tolerance and quality of life assessments. Cardiol J. 2010;17(2):166-71. 26. Administration DoHaATG. Australian Public Assessment Report for Ivabradine. 2010. 27. Whalley D, Kalman JM. Efficacy of the Selective Sinus Node Inhibitor Ivabradine for Treatment of Drug Refractory Inappropriate Sinus Tachycardia: Early Experience. Heart, Lung and Circulation. 2006;15S:S103. 28. Cappato R, Castelvecchio S, Ricci C, Bianco E, Vitali-Serdoz L, Gnecchi-Ruscone T, et al. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation. J Am Coll Cardiol. 2012 Oct 9;60(15):1323-9. 29. Benezet-Mazuecos J, Rubio JM, Farre J, Quinones MA, Sanchez-Borque P, Macia E. Long-term outcomes of ivabradine in inappropriate sinus tachycardia patients: appropriate efficacy or inappropriate patients. Pacing Clin Electrophysiol. 2013 Jul;36(7):830-6. 30. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Circulation. 2003 Oct 14;108(15):1871-909.


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eAcknowledgements: No financial declerations to make

Figure legend

Figure 1: Electrocardiographic examples showing important differential diagnoses for

Inappropriate Sinus Tachycardia. A. An example of the permanent form of junctional

reentrant tachycardia is shown. In this example, antegrade (atria to ventricles) conduction

occurs through the atrioventricular node (AVN) and retorograde conduction (ventricles to

atria) through the accessory pathway. Retorograde conduction is relatively slow resulting in

a long RP interval. This is most obvious in leads II and aVF. B. An example of the most

common form of AV node reentrant tachycardia is shown. Retrograde conduction is very

rapid, resulting in a P wave deforming the terminal portion of the QRS complex. This

manifests as a pseudo-r’ in V1 and pseudo-s’ in II, III and aVF. C. An example of ventricular

pre-excitation is shown with conduction over an atrioventricular accessory pathway fibre.

This results in an abbreviated PR interval and a delta wave (slurred QRS upstroke). D. An

example of focal atrial tachycardia is shown. Like A, this is also a long RP tachycardia. The

specific P wave morphology and polarity will depend on the precise location of the focus

along the crista terminalis.

Figure 2: Overview of sinus node action potential profile. The pacemaker potetial (diastolic

depolarization, If funny current) is responsible for the slow drift of the membrane potential

(millivolts, mV) towards threshold (-40 mV). Once threshold is reached, rapid inward calcium

(ICa) movement triggers membrane depolarization. Potassium efflux (Ik) subsequently

repolarizes the membrane back towards subthreshold potential. Ivabradine accesses the

cytoplasmic aspect of the If channel, specifically inhibiting the pacemaker potential.


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Table 1: Major studies of Ivabradine for the treatment of IST

Author Study Design Population Key Findings

Whalley, 2006(27)

Open label prospective evaluation. Treatment with Ivabradine and 7 months follow-up

7 patients with IST refractory to ≥2 drugs

Compared to baseline, significant reduction in mean, minimum and maximum 24 hour HR. Significant improvement in quality of life scores

Cappato, 2012(28)

Prospective randomized double-blind placebo-controlled cross-over evaluation. Treatment with placebo or Ivabradine for 6 weeks then cross-over

21 patients with IST

Compared with placebo, Ivabradine significantly reduced supine and orthostatic HR; reduced mean, minimum and maximum HR; increased exercise expenditure capability; reduced symptom severity scores

Ptaszynski, 2013(16)

Open label prospective evaluation. Treatment with metoprolol succinate for 4 weeks followed by Ivabradine

20 patients with IST resistant to previous therapy with either metoprolol tartarate or verapamil

Compared to metoprolol succinate, Ivabradine showed greater reduction in mean 24 hour HR, greater reduction in symptom severity scores and greater increase in exercise tolerance with treadmill stress testing

Benezet-Mazuecos, 2013(29)

Open label prospective safety and efficacy study. Treatment with Ivabradine twice daily, 5 mg or 7.5 mg dosage

24 patients with IST treated with Ivabradine and followed-up for 12 months

Ivabradine treatment significantly reduced (normalised) mean, maximum and minimum HR, and significant improvement in quality of life scores. At 12 months, 80% of patients remained free of IST criteria despite stopping the medication

Calo, 2010(23)

Open label prospective safety and efficacy study

16 patients with IST treated with Ivabradine and followed-up for 6 months

Compared to baseline, Ivabradine significantly reduced mean and maximum HR. Ivabradine increased exercise capacity on treadmill testing

Table 1: Symptoms assessed by SF36 and/or European Heart Rhythm Association symptom score grades (I-IV). Heart rate trends assessed by 24 hour Holter monitoring. Metoprolol tartarate is a rapid acting twice daily dosed beta-blocker, whereas the succinate salt is the slow release once daily dosed formulation. HR: Heart Rate


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eFigure 11: Electrocaardiographic differentiial diagnosees for Inapppropriate Siinus Tachyccardia


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eFigure 2

2: Overvieww of sinus node action potential pprofile.


inappropriate sinus tachycardia: focus on ivabradine · inappropriate sinus tachycardia is defined...

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