Best of heart failure

58 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. 6 months and benefit was reported as early as 2–5 days after initiation of therapy [ 19 , 22 ]. Three patients had failed alternate therapies for management of POTS, which included beta-blockers, calcium channel blockers, alpha- blockers, midodrine, and digoxin [ 18 , 21 , 24 ]. All eight patients reported improvement in dizziness, tachycardia, lightheadedness, and alleviation of syncopal episodes, although measurements of HR after the initiation of ivab- radine were not consistently reported [ 17 – 24 ]. Two case reports documented adverse reactions to ivabradine treat- ment: one mild transient visual disturbances and one allergic reaction [ 18 , 20 ]. Despite the mild visual distur- ban es, vabradine was continued because the patient experienced significant improvement in POTS symptoms [ 20 ]. No details of the allergic reaction were included in the publication [ 18 ]. 4 Discussion Based on the evidence presented in this review, ivabradine appears to be an effective treatment for lowering HR and providing symptomatic relief without affecting other car- diac functions in patients with POTS. The benefit of ivabradine was demonstrated in two prospective open-label trials, three retrospective cohort studies, and eight case reports which evaluated the use of ivabradine for POTS [ 11 , 13 – 24 ]. In the pre- and post-study, a single 7.5 mg dose of ivabradine alleviated symptoms of dizziness, blurred vision, and palpitations and lowered average post- tilt test HR from 118 bpm to 101 bpm, with the test per- formed 60–80 min after ivabradine administration ( P \ 0.01) [ 13 ]. With consistent twice daily dosing retro- spectively reviewed, symptomatic response was improved in 55–78% of the included pediatric and adult patients and HR was significantly lowered without any significant change in BP or major side effects [ 11 , 13 , 15 – 24 ]. In the only prospective chronic dosing study, 72% of patients had complete resolution or great improvement in symptoms and eight patients (32%) reported complete resolution of sy cope [ 14 ]. Ivabradine effectively improved symptoms of POTS in patients who had failed alternate therapies in the past. Specifically, the majority of patients had failed at least one treatment in the retrospective cohort studies, as well as in three case reports [ 11 , 15 , 16 , 18 , 21 , 24 ]. Ruzieh et al. documented that on average, three medications were trialed prior to starting ivabradine [ 16 ]. Similarly, prior to starting the open-label trial conducted by Barzilai and Jacob, three patients were taking fludrocortisone and six were taking propranolol for management of POTS. All of these patients were required to discontinue treatment 24 h prior to the tilt table testing without and with ivabradine [ 13 ]. Considering that many of these patients reported improvement of POTS symptoms from ivabradine use, it is feasible that ivabradine could be utilized in POTS patients who have failed alter- nate treatments. However, it is not clear if any patients were treatment-naı¨ve prior to the use of ivabradine for the treatment of POTS. Therefore, there is insufficient evi- dence to support preference of ivabradine over the agents recommended by the 2015 HRS expert consensus state- ment in those naı¨ve to pharmacologic treatment. Alternately, ivabradine was used as add on therapy for some patients with persistent symptoms of POTS while on alternate agents. Specifically, three patients responded to ivabradine in combination with fludrocortisone and 11 in combination with midodrine [ 11 , 14 ]. In other studies, concomitant medications were allowed; however, patients utilizing combination treatment for POTS were not dif- ferentiated in the results of these studies. Previous reports for POTS patients have suggested that using lower doses of multiple agents rather than maximizing a single agent may achieve optimal response [ 25 ]. Both fludrocortisone and midodrine have peripheral effects; therefore, combination therapy with ivabradine may provide further benefit for control of HR. Dosing in the case reports, cohort studies, and open- label studies, excluding the 7.5 mg single-dose study, ranged from 2.5 to 20 mg/day for up to 113 weeks. When reported, initial dosages ranged from 2.5 mg once daily to 5 mg twice daily, with the most commonly studied starting dosage being 5 mg/day in one or two doses. The mean maintenance dosage studied was approximately 9.4 mg/day. These starting and maintenance dosages are lower than those recommended by the European Medicines Agency (EMA) and the FDA for the treatment of symp- tomatic chronic heart failure: initiate ivabradine at 5 mg twice daily and increase to a maximum dosage of 7.5 mg twice daily [ 6 , 7 ]. Notably, both organizations do recom- mend decreasing to 2.5 mg twice daily if a patient expe- riences symptoms of bradycardia at a higher dosage [ 6 , 7 ]. Therefore, based on the literature currently available evaluating ivabradine for the treatment of POTS, it is reasonable to initiate at low dosages of 2.5 mg once or twice daily and to adjust on the basis of the patient’s response and tolerability [ 13 , 19 , 22 ]. A summary of rec- ommendations for the treatment of POTS can be found in Fig. 2 . The benefits of ivabradine in these studies are likely a result of the selective inhibition of the pacemaker I f current without adverse hemodynamic effects. Unlike traditional HR-lowering agents such as calcium channel blockers and beta-blockers, ivabradine has no effect on myocardial contractility, ventricular repolarization, or intracardiac conduction [ 26 ]. Orthostasis, which is a limiting factor for many ther POTS tre tment options, was not reported with Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome 201