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56 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 performed in 17 of the 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 ivabradine (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. not affect BP or cardiovascular vagal tone. No adverse drug reactions were reported [ 13 ]. Sutton et al. conducted a prospective open-label trial that included 25 patients who experienced a HR increas greater than 35 bpm during a tilt test if aged 19 or older, or an HR increase greater than 40 bpm if aged 18 year or younger [ 14 ]. All included patients were compliant with the fluid intake recommendation of 3 L/day, salt intake of 6 g/day, and physical counter measures for symptom management. Twenty-one patients (84%) were female and 23 patients (92%) experienced palpitations at baseline. The average age was 33 years (range 17–70 years), and the av rage duration of POTS symptoms was 9 years. Thirteen patients (52%) were taking midodrine at the time of inclusion. During the tilt test, all 25 patients experienced pre-syncope and palpitations and 1 patients (64%) had a profound fluctuation of BP of greater than 30 mmHg. Ivabradine was started at 5 mg/day and titrated up to Table 2 Summary of case reports evaluating outcomes of ivabradine in postural orthostatic tachycardia syndrome Author Patient age Sex Ivabradine dosage Treatment duration Outcome Adverse reactions Case details/notes Meyer et al. [ 17 ] 19 years old Female NR 3 months Alleviation of symptoms: tachycardia, postural palpitations, light- headedness NR Developed POTS following stressful event; also given psychosocial support Nakatani et al. [ 18 ] 42 years old Female 2.5 mg once daily NR Improved orthostatic symptoms, alleviation of syncope Allergic reaction (details NR) Previously unable to tolerate alpha-agonists, bet -blockers, calcium channel blockers, or digoxin Aliyev et al. [ 19 ] 30 years old Male 5 mg twice daily 5 days and 6 months Alleviation of syncopal episodes (in upright position and during carotid sinus massage), paroxysmal atrial fibrillation NR Patient had fluctuating HR associated with drop in BP prior to POTS diagnosis Khan et al. [ 20 ] 44 years old Female 5 mg twice daily 6 weeks No residual inappropriate sinus tachycardia Mild transient visual disturbances Pacemaker in place: HR from 107–140 down to 80–90. All \ 120 at 6-week checkup. Cont ued therapy despite ADR Oztunc et al. [ 21 ] 17 years old Female NR 6 mo ths No complaint of dizziness or t chycardia at follow-up NR First treated with m toprolol 1 g/kg/day for 2 m nths, midodrine 10 mg three times daily for 45 days without benefit. Information provided about i crease in HR and BP prior to, but not during, treatment Hersi [ 22 ] 25 years old Female 5 mg twic daily 2 d ys 4 months Alleviation of fatigue, weakness, palpitations, tingling and coldness in feet NR HR had increased from 80 bp to 139 bpm upon standing; average of 80 bpm after ivabradine was started. The patient also ran out of medicine, symptoms returned, then resolved again upon restarting Jamil- Copley et al. [ 23 ] 25 years old Female 5 mg twice daily 3 weeks Alleviation of sharp pain in head, palpitations, lightheadedness, syncopal collapsing episodes NR HR 100–146 before ivabradine, 90 bpm while on ivabradine Ewan et al. [ 24 ] 21 years old Female 2.5 mg twice daily then 5 mg twice daily NR Improved Fatigue Impact Score from 102 to 52 (range 0–160) Improved orthostatic grading scale score from 19 to 9 (range 0–20) Improved HR from 120–160 to 90–95 NR Unable to tolerate beta-blockers or verapamil in the past ADR adverse drug reaction, BP blood pressure, bpm beats per minute, HR heart rat , NR not reported Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome 199