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57 management of t making. The patie compassionate bas benefits and side e their parents. 2 Methods We evaluated pa institution for who February 2008 to pharmacy databas starting the medi POTS was specifi heart rate increase 120 bpm within t with symptoms significant orthost age at commence up-titration, reaso treatment, medica medications with worsening of sym and at follow-up cardiogram (EKG dine and at follo 2.1 Statistical An Normally distribut and standard devi were described w pendent t test was nificant level was Table 1 Demographi clinician’s stated indi starting ivabradine 60 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 dup reviewed to consisted of t spective cohor use for POTS summary of i studies, and c 3.2 Literatur Barzilai and single-dose, patients with [ 13 ]. Orthosta of at least 30 more than 2 during a hea rences. Patien nancy, uncont history of syst function. Eig recruited wit 31 ± 3 years, duration of P participants taking propra ticipants were MEDLINE (n=19) Records after dup removed (n=6 Titles and abstracts (n=61) Full text articles ass eligibility (n=4 Articles include qualitative analysis 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 20 mg/day as needed for symptomatic relief. The mean ivabradine dosage was 10.7 mg/day, and treatment dura- tion ranged from 2 to 40 months (mean duration 15 months). Repeat tilt test during or following ivabradine treatment was not completed. Response to ivabradine treatment was categorized as deterioration, no change, improvement of symptoms without abolition, or abolition of symptoms. Two patients (8%) discontinued ivabradine treatment prior to assessment: one due to pregnancy and one due to unspecified side effects. Of the remaining 23 patients, at follow-up, eight patients (34.8%) reported abolition of symptoms, ten (43.5%) had improvement in symptoms without abolition, and five (21.7%) reported no change. Overall, 18 patients (78.3%) experienced relief of POTS symptoms following ivabradine use, and three (13%) were able to discontinue midodrine after starting ivabradine. Two patients (8.7%) reported visual side effects, but both patients continued therapy and the side effects later resolved [ 14 ]. McDonald et al. [ 11 ] completed a retrospective cohort study that identified patients with POTS who were started on ivabradine therapy 2.5 mg once daily, with dose titra- tion at follow-up according to symptoms. A self-reporting assessment tool was developed to assess efficacy, change in symptoms, and side effects. Twenty-two patients were identified, but two patients were considered lost to follow- up due to a lack of documentation. Of the remaining 20 patients, each had tried at least one other medication prior to taking ivabradine, most commonly a beta-blocker. Fourteen patients (70%) returned the self-reporting assessment tool; medical record documentation was reviewed for the remaining six patients (30%). The mean ivabradine daily dose was 5 mg in one or two divided doses (range 2.5–15 mg/day), and the mean duration of treatment was 25 weeks (range 7–113 weeks). During follow-up, three patients (15%) took ivabradine in combi- nation with fludrocortisone and one (5%) used ivabradine in combination with midodrine. Eleven patients (55%) had continued ivabradine at the time data were collected. Based on the self-reporting assessment tool, all patients that continued ivabradine reported decreased palpitations and tachycardia and eight patients (57%) reported improvement in fatigue. Nine patients (45%) reported having discontin- ued ivabradine because of a lack of effect ( n = 6), side effect ( n = 2), or change to alternate agent ( n = 1). The side effects that led to discontinuation were mild, including dizziness ( n = 1) and increased fatigue ( n = 1). Two patients reported visual abnormalities of phosphenes, but did not discontinue therapy as a result of the disturbance [ 11 ]. Delle Donne et al. [ 15 ] recently completed a retro- spective cohort study that identified pediatric patients (less than 18 years of age) treated with ivabradine for POTS from February 2008 to June 2014. Twenty-two patients were identified, 15 of whom were female. All patients had adopted non-pharmacologic therapies for POTS, and a tilt test was performed to confirm POTS diagnosis. Fourteen patients (63.6%) were on at least one other medication for POTS prior to starting ivabradine, most commonly flu- drocortisone. Ivabradine therapy was initiated at 2.5 mg twice daily and titrated up to 7.5 mg twice daily based on symptomatic response. Median follow-up was 4.6 months. Mean HR was reduced significantly from 82.5 bpm to 71.3 bpm ( P \ 0.05). Five patients (22.7%) discontinued ivabradine, one due to worsening of symptoms, two for lack of improvement, and two for complete resolution of symptoms. Fifteen patients (68.2%) reported improvement of POTS symptoms. One patient experienced phosphenes, which resolved with dosage reduction from 10 mg/day to 7.5 mg/day [ 15 ]. Ruzieh et al. led a retrospective cohort study that included 49 patients with POTS who were treated with ivabradine at a syncope and autonomic dysfunction clinic between January 2010 and October 2016 [ 16 ]. Patients were started on ivabradine 2.5 mg twice daily and titrated based on symptoms. Three patients (6.1%) continued on 2.5 mg twice daily, 35 patients (71.4%) were titrated to 5 mg twice daily, ten patients (20.4%) took 7.5 mg twice daily, and one (2%) required 10 mg twice daily dosing. Thirty-eight patients (77.6%) reported overall improve- ment of POTS symptoms while taking ivabradine. On average, patients had tried 3.0 ± 1.5 medications prior to starting ivabradine, most commonly beta-blocker or cal- cium channel blocker (67.3%), or selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (57.1%). At least one medication for POTS was discontinued in 17 patients (34.7%). Ivabradine signifi- cantly lowered sitting and standing HR (78.1 ± 10.7 vs 72.5 ± 7.6, P = 0.01 and 107.4 ± 14.1 vs 95.1 ± 13.7, P \ 0.001, respectively). The most improved symptoms were palpitations (88.4%) and lightheadedness (76.1%). Sixteen patients (32.7%) stopped taking ivabradine (11 due to lack of response, two for cost-related reasons, and three after complete resolution of symptoms), but no pat ents discontinued due to side effects. Nine patients (18.4%) experienced phosphenes and four patients (8.2%) reported nausea [ 16 ]. Eight case reports were identified describing the safety and efficacy of ivabradine for POTS [ 17 – 24 ]. The patients ranged from 17 to 44 years of age, with an average age of 28 years, and seven patients were female. Four patients were treated with ivabradine 5 mg twice daily. One patient was started at 2.5 mg twice daily and titrated up to 5 mg twice daily, one patient received 2.5 mg once daily, and the exact dosing strategy was not discussed in the remaining two cases. Treatment duration ranged from 3 weeks to 200 M. E. Gee et al.