Best of heart failure

60 management of the patients or the clinicians’ decision- making. The patients had all been prescribed the drug on a compassionate basis by their clinician and after potential benefits and side effects had been discussed with them and their parents. 2 Methods We evaluated patients younger than 18 years in our institution for whom ivabradine had been prescribed, from February 2008 to June 2014. We used our institutional pharmacy database. We ascertained the indication for starting the medication and in particular those where POTS was specified. POTS was defined as a sustained heart rate increase of 30 bpm or increase of heart rate to 120 bpm within the first 10 min of orthostasis associated with symptoms of orthostatic intolerance and without significant orthostatic hypotension [ 6 ]. Gender, weight, age at commencement, dose at commencement and after up-titration, reason for discontinuation, follow-up, days of treatment, medication prior to starting ivabradine, and medications with ivabradine, outcome (improvement, worsening of symptoms), heart rate and QTc at baseline and at follow-up were evaluated. Heart rate and electro- cardiogram (EKG) were recorded before starting ivabra- dine and at follow-up. 2.1 Statistical Analysis Normally distributed data were described with the mean and standard deviation (SD), whereas non-parametric data were described with median and range. Student’s inde- pendent t test was used as appropriate. A statistically sig- nificant level was set at p \ 0.05. 3 Results From the pharmacy database, ivabradine was prescribed to 28 children \ 18 years; POTS was the indication to start ivabradine in 22. Their demographics are shown in Table 1 . All patients included in this study had adopted non- pharmacological therapies (e.g., increase in salt and fluid intake, counter pressure maneuvers, avoidance of precipi- tating factors). One (4.5%) had hypermobility syndrome and three (13.6%) confirmed Ehlers–Danlos syndrome. A tilt test was performed in all of these 22 patients. All 22 had an echocardiogram to exclude cardiac structural abnormalities. Twenty-four hour Holter moni- toring was perfor med in 17 of th e 22 patients (77%) showing no arrhythmia. Fourteen of the 22 patients (63.6%) were on at least one other medication for POTS prior to the introduction of ivabradi ne (Table 2 ). In four of 22 (18%), ivabradine was added to one other drug: flu- drocortisone in two patients and midodrine in two patients. Ivabradine was prescribed at the initial dosage of 5 mg/day in two divided doses. It was titrated up to 15 mg/day according to the control of symptoms. Ivabradine was up-titrated in 11 patients (50%). Mean (SD) dose of ivabradine after up-titration was 9.5 (4.1) mg, corresponding to 0.1 mg/kg/dose twice a day. EKGs after commencing ivabradine were available for retrospective analysis in 19 patients. 3.1 Follow-Up and Outcome Median follow-up was 4.6 (0.9–17) months. Six patients were followed up for less than 3 months. In four of them, ivabradine was discontinued: two for complete resolution of symptoms, one for worsening of the symptoms of syn- cope and palpitation (after 55 days). In one patient, Table 1 Demographics and the clinician’s stated indications for starting ivabradine POTS 22 patients Gender Female 15, male 7 Age at commencement, median (range) and mean (SD) 14.5 (11–17) years, 14.8 (1.6) years Dose after up-titration mean (SD), absolute and per kg 9.5 (4.1) mg, 0.1 mg/kg Follow-up median (range) 4.6 (0.9–17) months Duration of treatment median (range) 3.7 (0.9–17) months EKG available for retrospective analysis (number of patients) 19 Holter 24-h monitoring (number of patients) 17 Echocardiogram (number of patients) 22 Tilt test (number of patients) 22 Baseline heart rate, mean (SD) 82.5 (13.6) bpm Baseline QTc, mean (SD) 397.6 (20.2) ms EKG electrocardiogram, POTS postural orthostatic tachycardia syndrome, SD standard deviation 60 G. D. Donne et al. on, and palpitations, after st-tilt HR significantly without treatment to bradine administration d by 4 ± 1 bpm, but this reduction. Ivabradine did ic tachycardia syndrome Adverse reactions NR 8) t: 10) 1.7% 0% Visual side effects 9% ( n = 2); study discontinuation due to unspecified side effect 4% ( n = 1) : 1) 55% gue: ) Visual abnormalities: 10% ( n = 2) dizziness: 5% ( n = 1) fatigue 5% ( n = 1) : 15) 7.3% 1) Mild phosphenes: 4.5% ( n = 1) t: 38) : ness: Phosphenes: 18% ( n = 9) Nausea: 8.2% ( n = 4) M. E. Gee et al. application of some of the data. Lastly, for patients with an established diagnosis of POTS, information about duration of symptoms and prior treatment regimens was often not available. One additional limitation, not related to these studies, but related to off-label use of this recently FDA-approved agent, is cost. This is evidenced by two patients who dis- continued ivabradine therapy after insurance approval ended after 1 year in the Ruzieh et al. study [ 16 ]. With an average wholesale price for a one-year supply of medica- tion ranging from approximately US $3000 up to US $12,000 depending on dosage required, the traditional th rapies r commended in the 2015 HRS expert consensus statement with generic options are likely to be more accessible options for patients and prescribers in this era of prior authorization requirements [ 29 ]. No universal regimen has been identified that effectively treats all patients with POTS, and some patients are unable to tolerate the treatment options recommended by the 2015 HRS expert consensus statement because of increased fatigue, hypotension, and other adverse reactions [ 3 ]. Despite limited evidence, ivabradine is a promising therapy being considered for the treatment of POTS, especially owing to the lack of apparent effect on cardiovascular functions other than HR lowering [ 5 ]. Unfortunately, the data currently available is severely limited; only 132 patients in total were evaluated in the published reports included in this review. Therefore, a placebo-controlled, randomized clinical trial, or preferably a trial with an active comparator such as propranolol, is needed to further determine the role of ivabradine in the treatment of POTS. 5 Conclusions POTS remains challenging to treat because of the limited effective treatment options. The published data support the use of ivabradine for POTS, but at this time, only retro- spective and prospective open-label studies and case reports ar available. For patients who have symptomatic tachycardia and have failed other pharmacologic therapies, a trial of ivabradine is a reasonable option. Additional research is warranted to fully elucidate the role of ivabra- dine for the treatment of POTS and to identify the patients most likely to gain benefit from treatment. Compliance with Ethical Standards Conflict of interests Megan E. Gee, Alicia K. Watkins, Jamie N. Brown and Emily J. A. Young declare that they have no conflicts of interest th t might be relevant to the contents of this manuscript. Funding No external funding was used i the preparation of this manuscript. References 1. Raj SR. Highlights in clinical autonomic neurosciences: treat- ent insights for postural tachycardia syndrome and nappro- priate sinus tachycardia. Auton Neurosci. 2013;177:72–3. 2. Kavi L, Gammage MD, Grubb BP, Karabin BL. Postural tachy- cardia syndrome: multiple symptoms, but easily missed. Br J Gen Pract. 2012;62:286–7. 3. Sheldon RS, Grubb BP, Ols ansky B, et al. Hear Rhythm Society expert consensus statement on the diagnosis and treat- ment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12:e41–63. 4. Carew S, Connor MO, Cooke J, et al. A review of postural orthostatic tachycardia syndrome. Europace. 2009;11:18–25. 5. Raj SR. Postural tachycardia syndrome (POTS). Circulation. 2013;127:2336–42. 6. CORLANOR (ivabradine). US package insert. Thousand Oaks, CA: Amgen Inc; 2015. http://pi.amgen.com/ * /media/amgen/repository sites/pi-amgen-com/corlanor/corlanor_pi_hcp.pdf . Accessed 30 Oct 2017. 7. PROCORALAN (ivabradine). European Medicines Agency Report summary for the public. 2005. http://www.ema.eur pa.eu/ docs/en_GB/document_library/EPAR_-_Summary_for_the_public/ human/000597/WC500043585.pdf . Accessed 30 Oct 2017. 8. Riccioni G. Ivabradine: recent and potential applications in clinical practice. Expert Opin Pharmacother. 2011;12:443–50. 9. Oliphant CS, Owens RE, Bolorunduro OB, Jha SK. Ivabradine: a review of labeled and ff-label uses. Am J of Cardiovasc Drugs. 2016;16:337–47. 10. Dillinger JG, Maher V, Vitale C, et al. Impact of ivabradine on central aortic blood pressure and myocardial perfusion in patients with stable coronary artery disease. Hypertension. 2015;66:1138–44. 11. McDonald C, Frith J, Newton JL. Single centre experience of ivabradine in postural orthostatic tachycardia syndrome. Euro- pace. 2011;13:427–30. 12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9. 13. Barzilai M, Jacob G. The effect of ivabradine on the heart rate and sympathovagal balance in postural tachycardia syndrome patients. Rambam Maimoni es Med J. 2015;6:e0028. 14. Sutton R, Salukhe TV, Franzen-Mcmanus AC, C llins A, Lim PB, Francis DP. Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope. Europace. 2014;16:284–8. 15. Delle Donne G, Noguer FR, Till J et al. Ivabradine in postural orthostatic tachycardia syndrome: preliminary experience in children. Am J Cardiovasc Drugs. https://doi.org/10.1007/ s40256-017-0248-x . 16. Ruzieh M, Sirianni N, Ammari Z, et al. Ivabradine in the treat- ment of postural tachycardia syndrome (POTS), a single center experience. Pacing Clin Electrophysiol. https://doi.org/10.1111/ pace.13182 . 17. Meyer C, Mu¨hlsteff J, Drexel T, et al. POTS following traumatic stress: interacting central and intracardiac neural control? J Dia- betes Complicat. 2015;29:459–61. 18. Nakatani Y, Mizumaki K, Nishida K, Inoue H. Atrioventricular node ablation and pacemaker implantation for recurrent syncope in a patient with postural tachycardia syndrome (POTS). J Car- diovasc Electrophysiol. 2011;22:1284–7. 19. Aliyev F, C¸ eliker C, Tu¨rkog˘lu C, Uzunhasan I. Successful use of ivabradine in a case of exaggerated autono ic dysfunction. Turk Kardiyol Dern Ars. 2010;38:285–9. Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome 203