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52 SYSTEMATIC REVIEW Ivabradine for the Treatment of Postural Orthostatic Tachycardia Syndrome: A Systematic Review Megan E. Gee 1 • Alicia K. Watkins 1 • Jamie N. Brown 2 • Emily J. A. Young 3 Published online: 12 January 2018 This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018 Abstract Introduction Postural orthostatic tachycardia syndrome (POTS) impacts millions of patients, but there is currently no gold standard treatment for this condition. Ivabradine is a novel heart rate (HR) lowering agent that acts on the sinoatrial node cells by selectively inhibiting the If-current. Objective The objective of this systematic review is to evaluate the evidence for the efficacy and safety of ivab- radine for the treatment of POTS. Methods MEDLINE (from 1956 to August 2017) and EMBASE (from 1957 to August 2017) were queried with the following search term: ‘‘postural orthostatic tachycar- dia syndrome’’ OR ‘‘postural tachycardia syndrome’’ OR ‘‘chronic orthostatic intolerance’’ AND ‘‘ivabradine.’’ Articles in English with clinical outcomes of human patient(s) treated with ivabradine for POTS were included. Results The initial search identified 73 articles. After screening, 13 articles were included. Two prospective open-label trials, three retrospective cohort studies, and eight case reports evaluated the safety and efficacy of ivabradine in a total of 132 patients with postural tachy- cardia. Overall, ivabradine lowered HR and provided symptomatic relief of POTS without blood pressure low- ering. Dizziness, nausea, headache, and fatigue were the most common side effects and often did not lead to dis- continuation of treatment. Conclusion Based on this small sample, ivabradine appears to be a reasonable option for patients with POTS who have failed or are unable to tolerate other treatment options, however, but a randomized controlled trial in this population is needed. Key Points Postural orthostatic tachycardia syndrome remains difficult to treat given limited effective treatment options. Published data supports the use of ivabradine for POTS, but at this time, only open-label studies and case reports are available. For patients who have symptomatic tachycardia and have failed other pharmacologic therapies, a trial of ivabradine is a reasonable option. 1 Introduction Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia that is estimated to impact millions of patients in the USA. It is identified by the presence of frequent symptoms of orthostatic intolerance for at least 6 months accompanied by an increase in heart rate (HR) of at least 30 beats per minute (bpm) within 10 min of assuming an upright posture, but without orthostatic & Megan E. Gee megangee@buffalo.edu 1 Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, 508 Fulton Street (119), Durham, NC 27705, USA 2 Pharmacy Service, Durham VA Health Care System, 508 Fulton Street (119), Durham, NC 27705, USA 3 Pharmacy Service, VA Tennessee Valley Healthcare System, 1310 24th Avenue South (119), Nashville, TN 37212, USA Am J Cardiovasc Drugs (2018) 18:195–204 https://doi.org/10.1007/s40256-017-0252-1 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 s de ef ects 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 in ication 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 commenc g ivabradine were available for retrospective analysis in 19 patients. 3.1 Follow-Up nd Outcom 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 availabl 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.