Best of heart failure

54 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. for POTS were evaluated. Animal studies and articles written in languages other than English were excluded. The titles and abstracts of the search results were first screened for possible inclusion. The full texts of these reports were then reviewed to determine final eligibility for inclusion in the systematic review. Authors (MEG and AKW) indepen- dently performed the literature review and study selection. Any disagreements were resolved by a third author (JNB). 2.3 Data Extraction Authors, publication date, study design, study location, patient demographics, ivabradine treatment dose and dura- tion, prior medication use for treatment of POTS, con- comitant medication treatment regimens, clinical outcomes including subjective (improvement of symptoms) and objective (change in HR) measures, and ivabradine-related adverse drug events were extracted from each included study using a standardized data extraction process. 3 Results 3.1 Study Selection Figure 1 describes the literature search. Initially, 73 articles were identified. After screening titles and abstracts and removing duplicates, the full texts of 46 articles were reviewed to determine final eligibility. Final inclusion consisted of two prospective open-label trials, three retro- spective cohort studies, and eight case reports of ivabradine use for POTS in a total of 132 patients [ 11 , 13 – 24 ]. A summary of included prospective open-label trials, cohort studies, and case reports can be found in Tables 1 and 2 . 3.2 Literature Review Barzilai and Jacob conducted a prospective, open-label, single-dose, pre- and post-trial that included POTS patients with orthostatic intolerance for at least 6 months [ 13 ]. Orthostatic intolerance was defined as increased HR of at least 30 bpm without concomitant decrease of BP of more than 20/10 mHg within 10 min of standing or during a head-up tilt on at least three different occur- rences. Patients were excluded for active smoking, preg- nancy, uncontrolled thyroid or adrenal disorders, or any history of systemic illness that could influence autonomic function. Eight patients met inclusion criteria and were recruited within a year period. The average age was 31 ± 3 years, six patients were female, and the average duration of POTS symptoms was 2.6 ± 1 years. Three participants were taking fludrocortisone and six were taking propranolol at the beginning of the trial. All par- ticipants were required to stop these treatments at least MEDLINE (n=19) Embase (n=54) Records after duplicates removed (n=61) Titles and abstracts screened (n=61) Full text articles assessed for eligibility (n=46) Articles included in qualitative analysis (n=13) Records excluded for irrelevanc (n= 5) - Medication/treatment other than ivabradine (n=9) - Different disease state (n=5) - Language (n=1) Excluded articles (n=33) - Not original research (n=19) - Conference abstract (n=11) - Editorial (n=2) - No clinical endpoints (n=1) Identi�ication Screening Eligibility Included Fig. 1 Flow diagram for reference search and selection of articles for analysis Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome 197