Best of heart failure

50 vabradine was prescribed to was the indication to start ographics are shown in is study had adopted non- ., increase in salt and fluid vers, avoidance of precipi- d hypermobility syndrome hlers–Danlos syndrome. A f these 22 patients. ogram to exclude cardiac ty-four hour Holter moni- of the 22 patients (77%) rteen of the 22 patients other medication for POTS radine (Table 2 ). In four of ed to one other drug: flu- d midodrine in two patients. at the initial dosage of ses. It was titrated up to ntrol of symptoms. n 11 patients (50%). Mean p-titration was 9.5 (4.1) mg, se twice a day. EKGs after available for retrospective 9–17) months. Six patients 3 months. In four of them, wo for complete resolution ng of the symptoms of syn- 55 days). In one patient, patients ale 15, male 7 5 (11–17) years, 14.8 (1.6) years (4.1) mg, 0.1 mg/kg (0.9–17) months (0.9–17) months 5 (13.6) bpm .6 (20.2) ms , SD standard deviation G. D. Donne et al. 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 stat d 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. converting enzyme inhibitor or angiotensin receptor blocker, and a mineralocorticoid receptor agonist [ 2 , 14 , 15 ]. Off-label indications are POTS, inappropriate sinus tachycardia and heart rate reduction before computed tomography (CT) coronary angiography [ 16 ]. There is emerging evidence of the use of ivabradine in POTS. All the studies published are retrospective or case reports. Sutton et al. [ 4 ] reported marked benefit or com- plete resolution of symptoms in 72% of patients, and ivabradine was well tolerated. McDonald et al. [ 3 ] con- cluded that 60% of patients reported a symptomatic improvement; the drug was well tolerated. The most common reason for discontinuing ivabradine was lack of efficacy. Five of 22 patients reported side effects, leading to discontinuation in two patients. Khan et al. [ 17 ] reported a case of a 44-year-old woman with POTS and dual chamber pacemaker implanted because of intermittent complete heart block. Ivabradine was successfully used to lower heart rate. There was no evidence of POTS on repeat investigation; the pacemaker check showed a maximum heart rate of 120 bpm, and the 24-h tape showed appro- priate heart rate response. There was symptomatic benefit [ 17 ]. Until recently, very little was known about ivabradine in the pediatric population. Case reports have reported ivab- radine being used to treat junctional ectopic tachycardia [ 18 ] and cardiomyopathy induced by inappropriate sinus tachycardia [ 19 ]. Recently, Bonnet et al. [ 5 ] published a randomized, double-blind, placebo-controlled study. They evaluated 116 children with dilated cardiomyopathy. Dur- ing a 1-year follow-up, there was a reduction in heart rate and an increase in left ventricular ejection fraction and clinical status [ 5 ]. In our retrospective observational series, we report that ivabradine is well-tolerated and safe in patients younger than 18 years with POTS. One developed mild and dose- dependent phosphenes. This visual disturbance (flashing lights) is due to ivabradine interaction with the HCN1 isoform expressed in the retinal photoreceptor. The tran- ient change in visual sensation was observed in about 15% of adult patients following initial treatment with ivabradine [ 20 ]. It has been shown that it typically resolves during treatment [ 21 ]. As with the previous studies published in the adult population in POTS, we observed 68% improvement of the symptoms. 4.1 Limitations This is a preliminary and observational retrospective study of a small number of children prescribed ivabradine on a compassionate basis for POTS. It was purely descriptive and not randomized or blinded. Widespread implications must therefore be guarded until such time as a randomized controlled trial is published for this indication. With these caveats, at the dose used, it does appear to be safe and have some efficacy in children with POTS. As this was an observational study, there was no attempt to influence patient management. The tilt test and Holter 24-h record- ings were not repeated on ivabradine to confirm reduction in heart rate. 5 Conclusions From our limited preliminary experience, ivabradine appears to be a safe treatment for patients under 18 years of age with POTS. There is an improvement of symptoms in over two-thirds of our patients, a low incidence of phos- phenes, and no other obvious side effects. Further studies are needed to assess the efficacy and the safety of this drug in a randomized controlled setting for this indication. Acknowle gements We thank Khola Khan, Senior Pharmacist at the Royal Brompton Hospital for her input and help. Compliance with Ethical Standards This study was supported by th Clinical Research Unit of the Royal Brompton Hospital. Conflict of interest Grazia Delle Donne, Ferran Rose´s Noguer, Jan Till, Tushar Salukhe, Sanjay K. Prasad and Piers E. F. Daubeney declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. References 1. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dys- function (BEAUTIFUL): a randomised, double-blind, lac bo- controlled trial. Lancet. 2008;372:807–16. 2. Swedberg K, Komajda M, Bo¨hm M, et al. Ivabradine and out- comes in chronic heart failure (SHIFT): a randomised placebo- controlled study. Lancet. 2010;376:875–85. 3. McDonald C, Frith J, Newton JL. Single centre experience of ivabradine in postural orthostatic tachycardia syndrome. Euro- pace. 2011;13:427–30. 4. Sutton R, Salukhe TV, Franzen-McManus AC, et al. Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope. Europace. 2014;16:284–8. 5. Bonnet D, Berger F, Jokinen E, et al. Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart failure. J Am Coll Cardiol. 2017;70(10):1262–72. 6. Carew S, Connor MO, Cooke J, et al. A review of postural orthostatic tachycardia syndrome. Europace. 2009;11:18–25. 7. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node if channels by ivabradine. J Gen Physiol. 2002;120:1–13. 8. Fox K, Ford I, Steg PG et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular 62 G. D. Donne et al.