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53 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 hypotension [ 1 ]. This is substantially higher than the nor- mal increase of 10–20 bpm and minimal change in blood pressure (BP) that is seen in individuals without POTS. Typically, the compensation for a change to an upright position occurs with approximately 500 mL of blood descending from the thorax to the abdominal cavity and limbs. However, this regulatory mechanism fails in patients with POTS [ 2 ]. Patients with POTS often present with lightheadedness, palpitations, tremor, generalized weakness, blurred vision, exercise intolerance, sleep disturbances, migraine head- aches, or fatigue [ 3 , 4 ]. To appropriately diagnose POTS, alternative causes for postural tachycardia, such as pro- longed bed rest, medication use, and chronic debilitating disorders must be excluded [ 5 ]. A tilt-table test or 10-min stand test is usually implemented for a formal diagnosis [ 1 ]. POTS is often misdiagnosed as anxiety, panic attacks, chronic fatigue syndrome, or inappropriate sinus tachy- cardia because of the similarity between symptoms and clinical presentation of these conditions [ 2 ]. In 2015, the Heart Rhythm Society (HRS) released an expert consensus statement recommending the utilization of non-pharmacologic interventions as the first-line treat- ment for POTS [ 3 ]. These non-pharmacologic interven- tions may include discontinuing medications that might worsen POTS, increasing fluid intake to 2–3 L daily and increasing salt intake to 10–12 g daily. Patients should also wear compression stockings to reduce venous pooling and participate in regular exercise for aerobic reconditioning and resistance training. Presently, there is no pharmaco- logic treatment with a US Food and Drug Administration (FDA)-approved indication for POTS. The pharmacologic interventions included in the expert consensus statement are fludrocortisone, pyridostigmine, midodrine, and low- dose propranolol. Each of these agents has a class IIb recommendation, which is reflective of benefits equivalent to, or possibly exceeding, the risks of therapy. Clonidine and alpha-methyldopa received the same class IIb recom- mendation, specifically for patients with prominent hyperadrenergic features. Notably, all of these agents affect BP in addition to their HR-lowering effects, and as a result, orthostatic symptoms may be worsened by these pharma- cologic treatments [ 3 ]. Additionally, many of these agents have central nervous system (CNS) depressant effects, which further limits tolerability. A well-tolerated therapy that treats the physiologic problem of elevated HR without affecting BP is needed to improve quality of life in patients with POTS. Ivabradine is a HR-lowering agent that was approved by the FDA in 2015 with the labeled indication for reducing the risk of hospitalization for worsening heart failure in a highly selected group of patients with stable, symptomatic chronic heart failure with reduced ejection fraction [ 6 ]. However, this agent has been available for use in Europe since 2005 [ 7 ]. It acts on the sinoatrial node cells by selectively inhibiting the I f current in a dose-dependent manner [ 8 ]. As a result, the diastolic depolarization of sinoatrial node cells is slowed and HR is reduced. It does not affect myocardial contractility, and therefore, ivabra- dine has no significant effect on BP [ 9 , 10 ]. In clinical trials, ivabradine was well tolerated with minimal side effects. The most common adverse effects of ivabradine, compared to placebo, included bradycardia (10% vs 2%), hypertension (8.9% vs 7.8%), atrial fibrillation (8.2% vs 6.6%) and phosphenes or visual brightness (2.8% vs 0.5%). Phosphenes are a luminous phenomenon characterized by transient enhanced brightness such as a halo, image decomposition, or colored bright lights in a limited area of the visual field and are generally triggered by sudden variations in light intensity [ 6 ]. Ivabradine is not a rec- ommended agent in the 2015 HRS expert consensus statement. However, it is mentioned with positive results from one single-center, open-label study [ 3 , 11 ]. Notably, it was approved by the FDA only 1 month prior to publica- tion of the HRS statement, and was not yet available for use in the USA at that time [ 3 ]. The management of POTS can be challenging, and there is currently a paucity of tolerable, effective treatment options. A subset of patients may be unresponsive or unable to tolerate traditional therapies. Considering the mechanism of action for ivabradine, it may be a viable alternative for patients who develop hypotension or fatigue from alternate therapies. The objective of this article is to review available literature evaluating the efficacy and safety of ivabradine for the treatment of POTS. 2 Methods 2.1 Literature Search MEDLINE (1956 to August 2017) and EMBASE (1957 to August 2017) were queried with the following search terms: ‘‘postural orthostatic tachycardia syndrome’’ OR ‘‘postural tachycardia syndrome’’ OR ‘‘chronic orthostatic intolerance’’ AND ‘‘ivabradine’’. References for each included article were also evaluated for possible inclusion in the systematic review. The literature search was per- formed and described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 12 ]. 2.2 Study Selection Clinical studies and case reports were included if clinical outcomes of human patient(s) treated with oral ivabradine 196 M. E. Gee et al.