This article isprotected bycopyright. Allrights reserved. Accepted Article

Email: Fax: Phone: 2006 Australia, of Sydney,NSW, University K25 -Medical Foundation Building NHMRC Clinical Trials Centre Professor Anthony C. Keech Addressfor correspondence: Universityof Sydney, Sydney,NSW, Australia †Departmentof ,Alfred RoyalPrince article as doi: 10.1002/ differencesbetween version lead to this may been through the copyediting, typesetting, pagination andproofreading process, which This article hasbeen accepted for publication andundergone full peer review but has not +61 9565 1863 9565 1863 +61 Hany S. Abed, MBBS PhD†; Jordan Fulcher, MBBS†; Michael J Kilborn, MBBS PhD†; [email protected] +61 9562 5003 Inappropriate Sinus Tachycar imj.13093 Anthony C.Keech,MBBS, MClinEpi.†

and the Versionof Record. Please cite this Hospital and NHMRC Clinical Trials Centre, NHMRC Trials Clinical Hospital and dia: Focus on Ivabradine FocusonIvabradine dia: This article isprotected bycopyright. Allrights reserved. Accepted Article poorly tolerated. Ivabradine isanovel sinus nodeI Beta-blockers,generally considered thecorner oneffects quality oflife.significant adverse Cu of anunderlying physiological condition The stimulus. often takesa chronic course with by an elevation in (HR) accompanied by wide ranging symptoms, in the absence Inappropriate sinus tachycardiais (IST)anincompletely understood condition characterised Abstract examination ofthe evidencethe for role andeffi of IST.reviewThis provides an overview of and chronic stable , but mo the HR. Ithasfor thetreatment beenapproved Keywords: Inappropriate sinus ; Ivabradine Inappropriate IST prevalence and mechanisms, followed by an rrently there is noeffectivetreatment for IST. stone oftreatment,are often ineffective and re recently shown promise in the treatmentthe in promise re recentlyshown of beta-blocker refractory chronic systolic cacy ofivabradine in f “funnyinhibitorwhich reduces current” the treatment ofthe treatment IST. This article isprotected bycopyright. Allrights reserved. Accepted Article >100bpm at rest (with at rest a mean 24-hourheart >100bpm Heart Rhythm Society expert consensus statement definesa ISTas “sinus heart rate inta tobaccosmoking, pressure, blood activity, blockade or autonomic denervation) is indepe correlation meanwith age, intrinsic HR (HR undercomplete pharmacologic autonomic and underlying physiologicalstatus. Population st to thewide normalHRrange of variationwi There isnoformallyaccepted HRthreshold forth resting and HRexertional no withidentifiable Inappropriate sinus tachycardiadefined as is Introduction the estimates for Wolff-Parkinson-White syndrome (0.15-0.31%)(6). No differences were were differences No (0.15-0.31%)(6). syndrome Wolff-Parkinson-White for estimates the forIST, yieldi the definition 7 fulfilled cohort, for antagonists were onbetaadrenoceptor the condition. However,theoverall population The largest of itskind, the study rigorously reimbursement,described the prevalence and co randomlyAn Icelandic of study sampled patients ofIST Clinical Prevalence and Course heade ,light symptoms include associateddistressing symptoms ofpalpitat dness, dyspnoea and pre-syncope. andpre-syncope. dness, dyspnoea excluded differential diagnosesand mimicsof ions”(1, ions”(1, 4, 5). Other described commonly hypertension treatmen hypertension thin thepopulation, itsdependency onage(2) ng a prevalence of 1.16%.This is greater than a persistent non-paroxysmal elevation inthe rate >90 bpm not due to bpmnotdue >90 rate physiological or pathological stimulus(1). pathological physiological or ndentlyphysical associatedwithlevelsof ke of and body height(3). The 2015 andbodyheight(3). of caffeine ke was relatively small (604) and 149subjects (604) small was relatively urse of ISTthe abovedefinition(4). of using urse from insuranceregistriesfor hypertension e definition of IST. inpart,related Thise definitionof is, udies show that,inaddition toan inverse t. Of the 604 patient the604patient t. Of primary causes) and causes) and primary This article isprotected bycopyright. Allrights reserved. Accepted Article intake, physical activity levels and adiposity. The mean age and physicalactivity levelsadiposity.age andThemean intake, found between IST and control patients with rega of specific genetic abnormalities with IST. associated genetic of specific depolariinfluxand mediatedcalcium messenger antibodies has been hypothesised to result antibodies in patients withISTascompar tissue(12).node A small study hasidentified inintrinsic anHR towards elevation mediated than anabnormality of autonomic modulation(11). Someclinical studies have pointed investigators to believe that the condition ma Thisobservationpatients(10). andthe relative exaggeratedHR responseto isoprenaline in or their receptorshave been implicated,however this remains speculative(8, 9).Notably, an unsubstantiated(7). Peripheral andcentral neur has suggested halogenated hydrocarbon exposure The trigger andmechanism forthetachycardia in Mechanisms in IST there waspersistence ofsymptoms, elevatedresting HR andelevated averagedaily HR. development of tachycardia-mediated and survival. However, at follow-up, years, theoutlookfor 6.0±2.4 condition wa bias related to thecohort source (systemic arte pressurein the IST group was47±7years and ed to controls(11). The presence of these these of presence The to controls(11). ed fusion occurs in less than onethird ofoccurs inless fusion in receptoractivation functionandsecond greater plasma levelsofgreater betaadrenoceptor y represent a sinus node channelopathy rather 147±11 mmHg, respectively, noting the likely notingthe respectively, 147±11mmHg, by ATP sensitive potassium channels in channels in sinus by potassium sensitive ATP inefficacy ofbeta-blockade have ledsome s found to be benign, particularly for the rial hypertension). Aftera mean follow-up of ohormonal mediators of autonomic control control autonomic of mediators ohormonal sation. Asyettherehavebeen noreports IST isunknown. Expert anecdotal evidence rds toage, gender, smoking habits,alcohol as one possible cause, although this is this although cause, as onepossible

24-h ambulatory systolic ambulatory 24-h This article isprotected bycopyright. Allrights reserved. Accepted Article Differential Diagnosis patientswi in symptomatic differentials, accordancetheexpert consensus, withclin allude tonon-physiological phenomena assuch nocturnal lackof vagal predominance. In hour, 48-hour, 7-day or longer ambulatory monito and ambulatory cardiacrhythmare monitors required. lattermayThe beintheform 24- of assessment, laboratory(serum thyrotropin leve orpsychosis. Therefore, inaddition tachycardia such as anaemia, cardiac failure, infection, intake,thyrotoxicosis, Essential to the diagnosisIST is of exclusion ofunderlying causes for an severity ofthe tachycardia. severity may varyfrommildtosignificantly andweakness either chronically pre-syncope, syncope, dyspnoea, intolerance, dizziness, light-headedness, Inappropriate sinus tachycardiaoften presents andDiagnosis Presentation Clinical re-entry tachycardia (AVNRT)almost always have a sudden onset and offset. The 12-lead shownin Figure 1 treatment, may presentwith similarsymptoms Certain cardiac supraventricular [Figure 1] . Accessory pathway mediated pathway. Accessory SVT andatrioventricular nodal th a persisting daytimea persisting th sinustachycardia ical isdiagnosis made, after exclusion of to undertaking a thorough general medical disabling, and importantlymay notparallel the or in a relapsing and remittingor inarelapsing pattern. Their amenable (SVT), whichare to curative non-specifically with symptoms including ls and full blood count) tests, a 12-lead ECGfullblood count)tests,a12-lead ls and toElectrocardiographic IST. examples are rs which may reveal occult or arrhythmias occult reveal may which rs appropriate sinus This article isprotected bycopyright. Allrights reserved. Accepted Article condition ofautonomic dysfunction characte POTS and ISThaveoverlapping clinicalfeatures Orth is Postural toconsider condition Another may point toeitherISTorAT. rhythm.of tachycardiaand sinus Theonsetsympto a Pwave mo nodegenerate close tothe will sinus andwave axis morphology willoftenprovidevita terminalis or even within thesinus node in arising adjace IST, particularlywhenfromareas (AT)other onthe handmay (14). pathway ablation(13) promote atachycardia-mediated cardiomyopathy tachycardia rates aslow as 130bpm may mask in theright inferior paraseptal region and is This incessantformof children and teenagers is the permanent formof Onepathway conduction important duringSVT. of directionality on the depending complex, narrow QRS or be broad may SVT mediated excitation areabsent at ba Generally, ifaccessory the pathway conducts in duration at baselineifconducting antero in the often seen during pathwaysma SVT.Accessory are P-waves conducted retrograde and subtle atbaseline normal usually is AVNRT in ECG long RP SVT commonly utilises an accessory pathway which islocated pathwaywhich long RPSVTcommonly anaccessory utilises seline, and therefore it is the form ofre-entry. Although12-lead ECGP often drug refractory. chronicdrug nature and often Its rised byaresponse hyperadrenergic to ostatic TachycardiaostaticSyndrome as (POTS), both oftentimes be difficult to differentiate from the diagnosis for months and subsequently subsequently months and for diagnosis the y result intypical deltawavesandshortPR .is recognised a disorder This increasingly grade direction, and thereforegrade direction, it is manifest. nt to the sinusnode, such assuperior crista the retrogradethe direction, featuresofpre- pre-excitation syndrome mostly affecting reciprocatingjunctionaltachycardia (PJRT). l clues tothe AT site oforigin, an AT focus rphology very oridenticaltosimilar that ofrphology . The latter is reversible after accessory accessory after isreversible . The latter ms, in additionms, tootherclinical features, concealed.pathway Accessory This article isprotected bycopyright. Allrights reserved. Accepted Article modest. At an experienced centre, after amean the sinus nodezone inthese patients. The effectiveness of inISTis atbest symptoms. Limited experience existsfor surgical Invasive techniques are reservedfor patien which may alsorequire specific treatment(1). of overlap identified is There an beta-blockers. supporting anadvantagefor beta-blockers with intrinsic sympathetic activityover pure whilst minimising anti-adrenergic related adverse effects. However, there is no evidence Conventional Management Conventional for Strategies IST in IST bpmwhereas is rarely >100 upright positionfromInbeing supine. position, the supine theECG 12-lead in POTSpatients a inbe useful demonstrating HR which to symptomsand changes relationship therefore a detailed clinicalassessment (15). An HRresponseexaggerated toisoprenaline maybeseeninboth IST andPOTS, and diaphoresis and pre-syncope of dizziness, symptoms with posture, in change orthostatic example, pindolol orexample, pindolol occasionally trialled beta adrenoceptorantago troublesom particularly be may effects side often unsuccessfulin controlling IST symptoms The use ofnegativechronotropic agents such as beta-blockers and calcium antagonistsis

acebutolol). Theacebutolol). goal withthis approach is to supress elevatedHR 30 bpm HR rise (or tachycardia >120 bpm) on assumingthe bpm) >120 (ortachycardia HR rise 30 bpm the resting HR is often >100 bpm. isoften >100bpm. HR the resting is requiredto demonstratethe orthostatic ts highlydebilitated bydrug-refractory e inthis patient gro nists with intrinsic sympathetic activity (for sympathetic withintrinsic nists ISTin someinstances withanxiety disorders, andHR(16). Intoleranceto beta-blockade follow-up symptoms of4months, recurred or radiofrequency catheter modification of of modification catheter orradiofrequency occurin POTS. Ahead up tilt tabletestmay up. Clinicianshave This article isprotected bycopyright. Allrights reserved. Accepted Article patients with IST(24-26). withIST(24-26). patients addition, emerging evidence has shown ivabradine this is foruseinangina, approved although only covered bythePharmaceutical Benefit Sc fraction ejection (impaired systolic chronic of exercise toleranceinpatients withcoronary ar inadequatelycontrolled drug HR. The has been studiedfor itsquantitative impacton Ivabradine conduction andcomplete relianceon permanent pacing in this younger demographic. The ablate and pace strategyisoften undesirable inthe viewof sacrifice of atrio-ventricular complications. serious but uncommon are syndrome cava vena superior and injury nerve phrenic right complicationslow is butnotnon-trivial.Sinus control was not achievedin onethirdpatients of despiterepeat procedures. The risk of in 27% of patients deemed to have acute procedural success(17). Long term symptom contraindicationbeta-blocker to line agentforpatientswithchronic stable been approved has The agent on contractility. chronotropic througheffects areduced sinoatrial Ivabradine isanovel selective inhibitorca of Overview of Ivabradine s, or as add-on therapy to be anginaintolerant who are of,orhave a currently only as a private prescription.In currently onlyas a private rdiac ionic rdiac ionic channels whic ) heart failure(18-23). Cu heartfailure(18-23). ) node dysfunction requiring permanent pacing, in Australia since 2006 primarily asasecond primarily since 2006 in Australia heme (PBS) for its useinHeart failureand heme (PBS)forits tery and for its role in the treatment depolarisation rate, with negligible effects tobe ofpotentially significant benefit in ta-blockers in patients with in patients ta-blockers h results in negative rrently, Ivabradineis This article isprotected bycopyright. Allrights reserved. Accepted Article only theS-enantiomershowing voltag whichis strongly expressedin thesinus node channel known astheHyperpolarization-activate cation transmembrane gated voltage non-selective a through generated ismostly current known as theknown pacemaker as or“funny” current(I potentcyclicala drift ofthe membrane resting coupled(andcalcium),with a slowlyoutwarddiminishing potassium current.in Thisresults Sinoatrial nodalan cellshave innate automatici Pharmacology ofIvabradine its unique characteristics when compared toothercardiac membrane channels. The I inhibitors such as andverapamil conc increase plasmalevels. Additionally, inhibitors such as macrolide antibiotics, azole and proteaseinhibitors may by metabolism hepatic pass first to extensive of absence daily. Inthe twice mg and exertional HRare reduced byapproximatel coronary pressure. perfusion Attherapeuticdose in systemic observed are changes measurable surface electrocardiogramIn additionto (ECG). Ivab myocardial repolarisationor contractility. depolarization andthereby reduces node sinus inwardselectively inhibiting the intracellular aspectchannel, ofthe the cation movement. This slows the rate of pacemaker of This slowstherate movement. cation food,anoraldosehasonly e-dependentaffinity toHCN4/I the omitant use of moderately potentCYP3A4 may result in a combined pharmacokinetic drug blocksthe transmembrane channel pore, cytochrome P450 (CYP) 3A4. Potent CYP3A4 CYP3A4 Potent 3A4. cytochromeP450(CYP) region. Ivabradine is a chiralmolecule Ivabradineisregion. a with vascular resistance, cardiac or vascularresistance, output f radine does not affect ) ial towards depolarization threshold, and is a neutral effect on myocardial inotropy, no ty involvinga slow inward currentofsodium y 10 bpm, with a ceiling effect at doses of 20 doses of at effect 10 bpm,withaceiling y beating rate with no appreciable effects on [Figure 2] d cyclic nucleotide gated (HCN4) channel, s (5-7.5twice mg daily oral dosing), resting . It was dubbed. Itwas “funny” because of about 40% due about 40%bioavailability the QT interval on the the QTintervalthe on f channel. Accessing f

This article isprotected bycopyright. Allrights reserved. Accepted Article Contra-indicationsadverse and reactions performedat thisnadir state. and onthat basis, clinicalinto studies its and overall tobioavailability 70%.Trough plas other drugs, ortheir plasma levels.Food delays Ivabradine isaweakinhibitorofCYP3A4 andis interaction. (increased serum Ivabradine) andpharmacody adrenoceptor antagonist, (5.8%). The comparable to but somewhat lower thanthepr (<60 bpm) was estimated at 4.2% in hypotension whereas visualdisturbances areth reactions. The most common cardiovascul to Ivabradine isshown be welltolerated, ventricularpolymorphic tachycardia risk. used withcareful monitoringtoprevent ex conditions thatpredispose toanacquired long tachyarrhythmias, Ivabradine should avoided be generally in thoseconditions. Finally, in ofto thelack block. Due clinical studiesinto contraindicationthe however drug maybeused , andin sinus nodedysfunction. Atri Ivabradine isgenerally contraindicated in th with dose-dependent predictable withdose-dependent adverse quantitativeexerciseareeffect on tolerance ar adversereactionsare bradycardiaand cessive bradycardiaand exacerbation ofthe e presence of resting bradycardia (<60 bpm), its safety or efficacyin atrialor ventricular ma levels occur 12 hours after the last dose thelastdose after 12 hours occur levels ma namic (potentiation of bradycardia bradycardia effect) of (potentiation namic combination of beta-blocker and Ivabradine Ivabradine and of beta-blocker combination therefore unlikelytoinfluence metabolism of QT interval, Ivabradine should be avoided or avoided interval, Ivabradineshouldbe QT absorption but increases peak plasma levels plasma peak butincreases absorption e moste common non-cardiovascular effects. evalence of evalence bradycardia noted for the beta withcaution in first andAV seconddegree oventricular (AV) nodal disease isa relative arandomised clinical study(31). is This This article isprotected bycopyright. Allrights reserved. Accepted Article Role of Ivabradine in IST inIST Ivabradine of Role modificationof theirdailyactivities to accommodate forthisvisualdisturbance. treatment interruption(27). Lessthanpati 1%of self-resolving in >75% ofpatientswithina the vast majorityofpatients reportingato mild with benign be to appears effect peculiar This of brightness. level ambient the in changes consists of bright illuminations at the periphery of the visual field exacerbated by sudden adverse reactionoverallphenomenocommon isa of 17.9% ina randomised double-blind multi- use results in an additive risk of bradycardia, with the SIGNIFY study showing a prevalence phosphene visualeffects dosage despite reduction(23). standardtreadmill stress testing. Onepatient significant reductionin maximal andmedianHR aswell as workloadsgreater achievedon efficacy study in18 subjects showedthe drug of efficacy scope forthe and tolerability showed Several non-randomised labelopen studiesof tolerated. orcompleteresolution(27). In improvement Ivabradine inreducing minimum, meanand maximum HR inaddition to symptom experimental use in ISThasEarly emerged(25). pilotwork demonstratedthe effectiveness of With thedevelopmentof ivabradineand insigh matter of monthsmatter of without addition,the drugappearedtobewell centre clinical trial setting(19). The most centre Themost clinical trialsetting(19). to be well tolerated and withassociated a was excluded fromthe study dueto persistent short to intermediate follow-up duration ts into its pharmacologic mechanisms, some moderatelevel is The condition ofintensity. ents reported havingtoents stop treatmentor Ivabradine Ivabradine in IST. In2010, open an label n of visual phosphenes (14.5%)(27). This This (14.5%)(27). phosphenes visual of n dose modification or dose modification This article isprotected bycopyright. Allrights reserved. Accepted Article (CIBIST; Clinical Trials Identifier NCT0165713 Identifier Clinical (CIBIST; Trials The Ivabradine Versus Beta-blockers in the remodelling. cardiac structural and/or functional favourable through symptom suppressiononly butmay represen 80% ofpatients(29).observationThe latter ofyear cessation of 1 wa the drugafter therapy An open label study oflonger duration in2013showed favourable resultsand in addition, as compsuperior attenuation symptom symptomatology an ISTscorin Using specific significantly greater troublesome bradycardia showed a greater reduction in daytime HR re therapy. Although meanhour 24 HR reduction was similar between both agents, Ivabradine were switchedfrommetoprololbeta-blockers Pa in HRandquantitative symptomatology(16). acting metoprolol (succinate) to than 45%reportedcompleteresolution of exercise tolerance and a quantitative reduction impr significant HR.hour Thesestatistically reductionon exercise, 16 bpmreduction on standing and 11bpm reduction in mean 24 HR,18bpm bpm reductionin a12resting experienced 5or 7.5mg mg twicedaily) (either to placebo in21patientswithIST(28).After6 controll placebo randomised and a small In 2012 Ivabradine in 20 patients in 20 patients Ivabradine ared with metoprolol succinate. ared withmetoprololsuccinate. symptoms. In 2013, a study comparing long long comparing a study 2013, In symptoms. ovements wereovements associated withimproved Treatment ofInappropriateSinus Tachycardia points towardsa possible mechanism beyond g algorithm, Ivabradine treatment showed 6) is an open label non-randomised study non-randomised is anopenlabel 6) duction. Themetoprolol groupexperienced t preventiont disease progression ofthe weeks of takingIvabradine therapy,patients weeks succinate to Ivabradine after 4 weeks of of 4weeks after Ivabradine to succinate and hypotension requiring dosage reduction. reduction. dosage requiring hypotension and tients who hadIST refr s associatedmaintained with HRbenefits in in symptom severityofmore in symptom >70%. Overall, ed cross-over study compared Ivabradine Ivabradine ed cross-over compared study was changes performedassessing actory totraditional This article isprotected bycopyright. Allrights reserved. Accepted Article comparing Ivabradine to the long half-life Ivabradinethe longhalf-life to comparing et al(16),wepositthat consid satisfy conventionaldiagnostic criteria for IS BureauofStat age(Australian of years 15-65 subsidised prescription drugstoresidents of provides that Government Australian the of program PBS is a The PBS. by the of Ivabradine Metropolol succinate,we providea crude esti 47±7 years)(4). Based onthis andthe comparative study betweenIvabradine and Still et al putthe prevalenceat 1.16%with Inappropriate sinus tachycardiaan isuncommo inIST ifIvabradinewas subsidised for use Cost Implications ablation wasactivelyrecommendedagains trial) and removed recommendations for other recommendation fortheuseivabradine ofwithlevel B-Revidence (moderate randomised Societyexpert Rhythm (HRS) Heart 2015 the for catheter ablation, noting thatall three tr I class recommendation forbeta blockers, forclass calcium IIa channel blockers and class IIb supraventricular The last focusedACC/AHA/ESC Guideline Recommendations forIST Management modalities. Table 1 outcome ofHRreductionis primary shows key findings of several important of showsseveral keyofdifferentfindings studies IST management ering aworst case scenario,50%of patients being treated for expected to be released in2016. expected to be released beta-blocker, bisoprol beta-blocker, preponderancein middle agedadults (mean age t with level E (consensus) evidence(5). evidence(5). level E(consensus) t with eatments had level Cevidence(30). However in T.Based on comparative data fromPtaszynski istics, 2010), 184,440 individuals could feasibly could feasibly 184,440 individuals 2010), istics, Australia. Of the 15.9 million Australians aged Australians Of15.9 million Australia. the consensus statement assigned a Class IIa IIa aClass assigned statement consensus mate ofcumulative costsincurred for funding n condition. Epidemiological estimates from pharmacotherapies. Inaddition,catheter guidelines inarrhythmia 2003 provided a ol. ThephaseIIIstudy This article isprotected bycopyright. Allrights reserved. Accepted Article can tolerate. The Europeancan tolerate.The MedicinesAgency had the HRatset cut-off 75beatsper minute of atleast70 beats per minute andalsotakingbeta-blockersare at the highestthey dose Ivabradine forpatients who have symptomsof he Ivabradine. IST couldrequirestep-up therapyfromeither with refractoryMoreover, symptoms. inour experience,treatment efficacious in this modificationof the node, sinus subsequently of treatment optionth forISTwouldlikelynegate should be emphasized thatthe availability channel and calcium Thisblockers antagonists). 92,220 to may model failure be used pati for the961,250 fundingIvabradine cost for [AIHW], (AIHW, 2012)and276,250 heart diseaseandfail cardiac at65%for Ivabradi conservatively estimated effectiveness ratio (ICER) expressed as acost/quality adjusted Life Year (cost/QALY)is the million by cost to government$10-30 at of Ivabradine forfunding Committee (July 2012) recommendations submitted by Servier Laboratories Australia Pty Ltd to the PBS Advisory a HR Ivabradine areforNYHAIIorIIIsystolic class chronic andheartfor stable systolic angina failure.indications Current PBS subsidy for thesameindication. InAustralia, Ivabradine ≥ 77 beats per minute, despite maximum tolerated beta-blocker dosage. Economic Economic dosage. beta-blocker tolerated maximum despite minute, per 77 beats symptomatic

The Food and DrugAdministration of patientswithIST refractoryto ure were 685,000 (Australian Inst ure were 685,000 (Australian the anticipated costsforfundin 2011) respectively. Therefor 2011) of Ivabradineas a potentially efficacious ne. In 2007-08, the prevalence ofischaemic ne. 2007-08,theprevalence In 5 years of listing. The incremental The cost 5 yearsoflisting. heart failure (LVEF < 35%) in sinus rhythm,with in <35%)sinus (LVEF failure heart beta-blockade orca beta-blockade e need forinvasive radiofrequency catheter 5 year estimate would be$1-2.9million. It would 5yearestimate ents with ischemic heart orents with ischemic disease heart cardiac is approvedfor use in refractory chronic fsetting invasive treatmentcosts in patients for systolic heart failure, estimated net a for systolic estimated heart failure, the UnitedStates recentlyapproved art failure that are witharestingHR failure thatstable art currentlyused pharmacotherapy (beta g Ivabradineforthe estimated itute of Health and Welfare e, the $10-30 million 5 year lcium antagonists to This article isprotected bycopyright. Allrights reserved. Accepted Article Conclusion Conclusion of sickdays, unemployment and disabilityclaims. younger patient population can reduce indirect economic costsassociated with the number IIa, LevelIIa, B-R evidence, reflectsthe progressivel However the updated HeartRhythm Society guidelinesrecommending IvabradinewithClass examiningplacebo controlledstudies effi the responsive patients.Currently there are no much asapotentialtherapy promise ofchoice a chronic condition becomingoften clinically amelioration. The drug is well tolerated and appears to carry a lower proarrhythmia risk. For quantitative improvementin exercise ca procedures. Insmallclinicalstudies,Ivab Catheter ablation remains an tech evolving benefit and effectprofilea significant adverse beta-blockers. Despite some effect at reduci to POTS,animportantopposed differential di node channelopathy in origin rather than a Whilst it course. remains on ill-defined acellular particularly effort tolerance and personal econ due to its predilectionin theyoung, ithas the the general adult population. Theconditionha aInappropriatewi condition sinustachycardiais pacity and subjective symptomburden radine hasshown benefitinHR reduction, nique withnique modest despite multiple results large prospective randomised double-blinded disease ofdisease alteredautonomic modulation (as ng HR, these agents appear to have limited cacy of the various treatmentmodalities. various cacy ofthe problematic in management, Ivabradine shows shows Ivabradine inmanagement, problematic agnosis). The mainstay of therapy has been potentialadversely impactdailyactivities, to inthisactiveofpatients. younger group s awide spectrumof symptom severity and omicproductivity, despite overall its benign for beta-blocker intolerant or sub-optimally y accruing evidence base foritsy accruingevidencebase use all above th a best estimate prevalence of 1.16% in prevalenceof1.16%in best estimate th a level, it appears that IST is probably a sinus This article isprotected bycopyright. Allrights reserved. Accepted Article References option.relatively inexpensivetreatment prescriptionsuitability for ivabradi subsidy, significant physiological andfunctionalimpr other conventionaltreatment Given options. 15. Raj SR. Postural tachycardia syndrome (P syndrome tachycardia Postural SR. Raj 15. junctional persistent of course Clinical 2nd. M, Dick F, Morady MJ, Silka PC, Dorostkar 1999 Feb;33(2):366-75. JCardiol. Coll Am tachycardia. reciprocating 14. Jan;8(1):21-8. 2006 Europace. ablation. catheter P,Bo F,Defaye Halimi R, Weber A, Meiltz of radiofrequency results and features peculiar adults: in tachycardia reciprocating junctional 13. Jun;13(6):557-62. 2002 Electrophysiol. Cardiovasc Impaired al. et J, Hartikainen R, MJ, Kettunen Koistinen KE, HV,Airaksinen Huikuri Still AM, in to response chronotropic negative 12. Heart Rhythm. 2006 Oct;3(10):1182-6. 2nd, Ol BP, Grubb RS, Sheldon 5. Mar;7(2):104-12. al. et Y, Kesaniemi M,Antero Ikaheimo H, Kauma A, Ylitalo P, Raatikainen Still AM, 2005 Europace. sinus tachycardia. inappropriate of course natural and characteristics Prevalence, 4. Aug;66(8):775-9. Kristal-Boneh E, HarariWeinstein G, Y, GreenMS. Factors affecting differencesin supine, 1995 Med. Environ Space Aviat Study. CORDIS Israeli the rate: heart standing and sitting, 3. d and range Thenormal D. JoseAD,Collison Cardiovasc Res. 1970 Apr;4(2):160-7. Feb 2. 2013 Cardiol. Coll JAm tachycardia. sinus Inappropriate RM. B,Sullivan Olshansky 26;61(8):793-801. 1. 11. Chiale PA, Garro HA, Schmidberg J, Sanchez RA, Acunzo RS, Lago M, et al. Inappropriate sinus sinus Inappropriate al. et M, Lago RS, Acunzo RA, J,Sanchez HA, Schmidberg PA,Garro Chiale toan may tachycardia berelated 11. Morillo CA, Klein GJ,Thakur RK, Li H, Zardini M,Yee R. Mechanismof 'inappropriate' sinus bal sympathovagal Role of tachycardia. 10. Dec;13(4):241-51. 2008 Ther. Pharmacol J Cardiovasc years. 50 = > or participants healthy in darifenacin and study tolterodine with crossover double-blind, Egerma J, U, Brum B,Ebinger Olshansky placebo-controlled, a randomized, rate: heart on drugs antimuscarinic of effects pharmacological 9. regulation C.Peptidic Lambert P, Beaulieu Mar;37(3):578-85. 1998 Res. Cardiovasc system. nervous 8. of mechanism Apossible JA, etal. J,Vitali Xu DP, Campbell S, Iravanian Jesus JiaoVR, Z, De Oct;41(4):698-705. 2006 Cardiol. Cell JMol arrhythmias. sensitization cardiac halocarbon-induced 7. 14;344(24):1823-31. T,Kari AS, Gollob Tang MS, Gollob MH,Green gene responsiblefor familial Wolff-Parkinson-White syndrome. NEngl2001 JMed. Jun 6. Jun;12(6):e41-63. 2015 Rhythm. Heart syncope. vasovagal and tachycardia, sinus inappropriate syndrome, tachycardia postural of treatment and diagnosis onthe statement consensus expert society rhythm immunologic disorder involving card involving disorder immunologic shansky B, Calkins B, ShenWK, H, shansky ance. Circulation. 1994 Aug;90(2):873-7. Aug;90(2):873-7. 1994 Circulation. ance. ne may well represent represent ne maywell rk M, Viegas A,RekedaL.Differential rk M, Viegas ovement withivabradine, when considering patients with inappropriate sinus tachycardia. J tachycardia. sinus inappropriate with patients OTS). Circulation. 2013 Jun 11;127(23):2336-42. 11;127(23):2336-42. Jun 2013 Circulation. OTS). veda S, Tavernier R, et al. Permanent form form of Permanent et al. R, S, Tavernier veda the low prevalence ofIST and evidence for of heart rate and interactions with the autonomicinteractions and withthe rate of heart eterminants of the intrinsic heart rate ineterminants of intrinsicheart the man. rate be A, Ali Hassan AS, et al. Identification of a Identification of et al. HassanAS, Ali A, be Brignole M, et al. 2015 2015 heart M,etal. Brignole iac betaandrenergic receptors. a cost-effective and a cost-effective and This article isprotected bycopyright. Allrights reserved. Accepted Article Guidelines (Writing Committee to Develop toDevelop Guid Committee (Writing Guidelines European the and Guidelines Force onPractice Colleg of American the a report executive summary: AJ,etal. Camm H, Alpert JS,Calkins EM, MM, Aliot Scheinman C, Blomstrom-Lundqvist ACC/AHA/ESC guidelinesfor the management of patients with supraventriculararrhythmias-- 30. Jul;36(7):830-6. 2013 Electrophysiol. Clin Pacing patients. inappropriate Benezet-Mazuecos J, JM, Rubio Qu Farre J, sinu in inappropriate term outcomes ivabradine of 29. 9;60(15):1323-9. Oct 2012 Cardiol. Coll Am J evaluation. crossover double-blind, placebo-controlled, randomized, Bianco C, S, Ricci Castelvecchio R, Cappato with patients in ivabradine of efficacy Clinical 28. Circulation. 2006;15S:S103. Whalley D,Kalman JM. Efficacy ofthe SelectiveSinusInhibitor Node Ivabradine for and Lung Heart, Experience. Early Tachycardia: Sinus Inappropriate Refractory of Drug Treatment Administration Publ Australian DoHaATG. 27. 26. and quality tolerance exercise Holter monitoring, with four patients in ivabradine of Efficacy FP. Ayma LS, Urondo FP, E, Comes Kaplinsky electrocardiographic, on based experience month-long three a tachycardia: sinus inappropriate 25. 2010 Dec;382(5-6):483-6. ZellerhoffB, Felix Krull Hinterseer M, S, Pharmacol. Arch Schmiedebergs Naunyn tachycardia. sinus inappropriate with patients in Ivabradine 24. Sep;7(9):1318-23. ivabradine of Efficacy al. et L, E, Sciarra A, deRuvo A,Martino Sette M, Rebecchi Calo L, 2010 Rhythm. Heart sinus tachycardia. inappropriate affected by in patients administration 23. po ofthe study characteristics baseline trial of randomized study: The BEAUTIFUL M. Tendera PG, Steg K, Fox I, R,Ford Ferrari - dysfunction systolic left ventricular and arterydisease coronary stable with patients in ivabradine 22. Aug;34(29):2263-70. 2013 J. Heart Eur trials. SHIFT and the BEAUTIFUL Bohm M, Robertson I, Ford M, K,Komajda Fox patients withleft-ventricular systolic dysfunction:a pooledanalysis of individual patient data from 21. 2010 Jan;12(1):75-81. the SystolicFailure Treatment Heart with the I(f) Swedberg K, Komajda BohmM, M, Borer JS,Ford I,Tavazzi L. Rationale and design ofa failure: heart chronic in ivabradine of trial outcome placebo-controlled double-blind, randomized, 20. 11;376(9744):875-85. Swedberg K, Komajda BohmM, M, Borer JS,Ford I,Dubost-Brama A, et al. Ivabradineand 2010 Sep Lancet. study. placebo-controlled a randomised (SHIFT): failure heart chronic in outcomes 19. e6. Oct;166(4):654-61 Am J.2013 Heart failure. heart clinical without artery disease coronary stable with in patients ivabradine of trial controlled placebo- double-blind, a randomized, trial): (SIGNIFY disease artery coronarY with patients in JC, Tendera PG, Tardif FoxK,Ford I, Steg morbidity- the assessInG Study the of characteristics 18. Feb;35(2):451-7. 2000 Cardiol. Coll JAm mapping. activation by guided tachycardia sinus inappropriate of ablation 17. Man KC, KC, Knight B,Tse Man MichaudHF, Pelosi F, 17. Jan;15(1):116-21. 2013 Europace. therapy. pharmacological vs. succinate Metoprolol JK. T, Wranicz Klingenheben J, Ruta K, Kaczmarek P, Ptaszynski ivabradine inthe oftreatment inappropriatesinus 16. Circ Arrhythmias). Supraventricular ulation. 2003 Oct 14;108(15):1871-909. 14;108(15):1871-909. Oct ulation. 2003 pulation. Cardiology. 2008;110(4):271-82. 2008;110(4):271-82. pulation. Cardiology. inappropriate sinus tachycardia: a prospective, prospective, a tachycardia: sinus inappropriate Society of Cardiology Committee for Practice Committee ofSociety Cardiology Schulze-Bahr E, Fabritz BreithardtL, G,et al. elines for the Manageme M, Ferrari R. Rationale, design, and baseline baseline and design, Rationale, R. Ferrari M, Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. Fail. Heart J Eur (SHIFT). Trial Ivabradine Inhibitor ic Assessment Report for Ivabradine. 2010. 2010. Ivabradine. for Report ic Assessment of life assessments. Cardiol J. 2010;17(2):166-71. J. 2010;17(2):166-71. Cardiol life of assessments. E, T,et Vitali-Serdoz al. L, Gnecchi-Ruscone s tachycardia patients: appropriateefficacy or inones MA,Sanchez-Borque P,MaciaE. Long- tachycardia in patients unresponsive to previous toprevious unresponsive patients in tachycardia e of Cardiology/American Heart Association Task Task Heart Association of Cardiology/American e GF, Flemming M, et al. mortality beNefits of of the If beNefits inhibitor ivabradine mortality M,et al.Effect Borer ivabradine JS, of in nt of Patients With Patients With of nt Radiofrequency catheter catheter Radiofrequency This article isprotected bycopyright. Allrights reserved. Accepted Article Inappropriate Sinus Tachycardia.Inappropriate SinusA. Figure 1:Electrocardiographic examplesshowing important differential diagnoses for Figure legend Acknowledgements: ( (millivolts, mV)towardsthreshold Once (-40 mV). cytoplasmic aspect of thecytoplasmic aspectof repolarizes themembrane back towards subthr depolarization, a long RP interval. This is most obvious leadsin II and aVF. atria) through pathway. the accessory Retorograd occurs throughtheatrioventricularnode (AVN reentrant tachycardiais this examplshown.In Figure 2: thecristaalong terminalis. Pspecific wave morphology and polarity will example of focal atrial tachycardia is shown.Like this A, is also alongRP tachycardia. The This resultsinanabbreviatedPRinterv pre-excitation is shown with conduction over asa manifests pseudo-r’ V1in andin pseudo-s’ II, III andaVF. deformingthe Pwave in a rapid, resulting ofcommonform AVnode reentrant tachycardi I Ca ) movementtriggers membrane depolarization. efflux( Potassium

Overview ofsinusnode actionpotentialprofile. I f funnycurrent)foris responsible the No financial declerationsto make I f channel, specifically inhibiting the pacemaker potential.

An example oftheperman al and a delta wave (slurred QRS upstroke). upstroke). QRS (slurred wave and a delta al terminal portion of theQRScomplex. portion terminal This depend on the precise location of the focus an atrioventricularaccessory pathway fibre. e, antegrade (atria to ventricles) conduction to antegrade(atria e, ) andretorograde conduction(ventriclesto a is shown. Retrograde conduction is very eshold potential.Ivabradine accessesthe threshold is threshold reached, rapid inward calcium e conduction is relatively e resultingin relatively slowconduction is slow driftslow ofthe membrane potential

Thepacemakerpotetial (diastolic B. Anexample of themost C. ent form junctionalof An exampleof ventricular I k ) subsequently D.

An This article isprotected bycopyright. Allrights reserved. Accepted Article whereas the succinate salt is the slow release once daily dosed formulation. HR: Heart Rate Heart HR: Rate formulation. dosed daily release once slow isthe salt succinate whereas the dosed twicebeta-blocker, daily acting arapid is tartarate Metoprolol monitoring. by 24 Holter hour trends assessed Author Study Design Population Key Key 2006(27) Whalley, Findings Author Study Population Table 1:Major studiesofIvabradine forthetreatment ofIST Design Table 1: 2010(23) Calo, 2013(29) Mazuecos, Benezet- 2013(16) Ptaszynski, 2012(28) Cappato, Symptoms assessed SF36 by Eu and/or months follow-up months follow-up and7 Ivabradine with Treatment evaluation. Open labelprospective safety and efficacy study Open labelprospective dosage mg or 7.5 mg daily,5 twice Ivabradine with Treatment safety and efficacy study. Open labelprospective Ivabradine for 4weeks followed by with metoprolol succinate Treatment evaluation. Open labelprospective then cross-over for weeks or Ivabradine 6 with placebo Treatment evaluation. cross-over controlled double-blind placebo- Prospective randomized ropean HeartRhythmAssociationsymptomgrades score (I-IV).Heart rate refractory to 7 patients with IST months months and followed-up for 6 withIvabradine treated 16 patients with IST months and followed-up for 12 withIvabradine treated 24 patients with IST metoprolol tartarate or eithertherapy with previous to resistant 20 patients with IST 21 patients with IST ≥ 2 drugs drugs 2 scores of life inquality improvement Significant hour HR. minimum and maximum 24 mean, in significant reduction Compared tobaseline, testing exercise capacity on treadmill increased Ivabradine HR. andmaximum reduced mean significantly Ivabradine Compared tobaseline, the stopping despite criteria ofIST free remained of patients 80% months, At of 12 quality life scores. significantin improvement HR, and minimum and maximum mean, (normalised) reduced significantly treatment Ivabradine testing stress tolerance withtreadmill increasegreater inexercise scoresand severity symptom in reduction greater hour HR, in reduction mean 24 greater succinate, Ivabradine showed Compared tometoprolol severity scores capability; reduced symptom exercise expenditure HR;increased maximum mean, minimum and orthostaticreduced HR; and supine reduced significantly Ivabradine Compared with placebo, This article isprotected bycopyright. Allrights reserved. Accepted Article Figure 1 1 : Electroc a rdiographi c different i al diagnos e e s forInap p p ropriate S i nus Tachy c ardia

This article isprotected bycopyright. Allrights reserved. Accepted Article Figure

2 2 : Overvie w of sinus n ofsinus ode action potential potential p rofile. rofile.