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Highlights in clinical autonomic neurosciences: Treatment insights for postural tachycardia syndrome and inappropriate sinus tachycardia
Autonomic Neuroscience: Basic and Clinical 177 (2013) 72–73
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Highlights in clinical autonomic neurosciences: Treatment insights for postural tachycardia syndrome and inappropriate sinus tachycardia Prepared by: Satish R. Raj ⁎ Autonomic Dysfunction Center, Departments of Medicine & Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
Section Editor: Roy Freeman Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA
This clinical update will focus on articles about the treatment for disorders of sinus tachycardia. The first article assesses the utility of urinary sodium excretion to predict response to dietary sodium intake in patients with postural tachycardia syndrome. The second article is a well-conducted clinical trial of ivabradine for inappropriate sinus tachycardia.
Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome. Zhang Q, Liao Y, Tang C, Du J, Jin H. (Beijing, China) J Pediatr. 2012; 161: 281−284
Article summary The authors sought to investigate whether 24-hour urinary sodium excretion could be an indicator of the effectiveness of salt supplementation in children with postural tachycardia syndrome (POTS). The patient group comprised 30 children with POTS, and the control group comprised 10 healthy children. Serum sodium and 24-hour urinary sodium excretion were measured in all children, and the relationship between 24-hour urinary sodium and symptom severity was analyzed in the 30 patients. At 1 month after initiation of salt supplementation, the receiver operating characteristic curve was used to explore the probability of correctly discriminating responders to salt supplementation from nonresponders using 24-hour urinary sodium excretion as an indicator. Patients with POTS had lower 24-hour urinary sodium excretion than controls (P = 0.022). Symptom severity was negatively correlated with 24-hour urinary sodium excretion (OR, − 0.754; P b 0.001). The receiver operating characteristic curve demonstrated a sensitivity of 77% and specificity of 93% for correct prediction of responders and nonresponders to salt supplementation when a 24-hour urinary sodium excretion of 124 mmol/24 h was used as the cutoff value.
⁎ AA3228 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2195, USA. Tel.: +1 615 343 6499; fax: +1 615 343 8649. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.06.008
Commentary POTS is a disorder in which many patients have been found to be hypovolemic. Even without that formal determination in an individual patient, standard medical therapy involves advising patients to augment their dietary sodium intake. This has been done absent significant evidence that sodium intake expands the plasma volume in these patients. Of note, salt supplementation runs counter to the population health advice of the American Heart Association, which has been working for many years to decrease societal dietary sodium intake. This study from Beijing has attempted to address this void. The authors studied 30 children with POTS and 10 healthy children. Each subject underwent a 24-hour assessment of urinary sodium excretion, and an assessment of symptom severity using a simple, custom grading system. Salt supplementation (5–7 g/day) was then initiated and the response was assessed 30 days later in the POTS patients. Not surprisingly, POTS patients had lower urinary sodium excretion than the healthy control subjects. Further, there was an inverse correlation between the severity of orthostatic symptoms and 24-hour urinary sodium excretion. With minor variations, if the patient is following a stable diet then the 24-hour urinary sodium excretion likely reflects the sodium intake over the day. Therefore, these data can be interpreted as stating that POTS patients with a lower dietary sodium intake had worse symptoms than those patients with higher dietary sodium intake. When given a relatively fixed amount of salt supplementation, those patients with a lower baseline sodium excretion (and presumably lower sodium intake) improved significantly. On the other hand, those patients with a higher sodium excretion (N 124 mmol/day) did not respond as well to further supplementation with sodium. Intuitively, those patients who follow a very sodium restricted diet and have orthostatic symptoms improve when their sodium restriction is eased by consuming more dietary salt. These data also suggest that the benefits of sodium supplementation may not extend to all of our patients, specifically, that those patients who already consume a moderate amount of sodium (N 124 mmol/day) do not benefit from further supplementation. Importantly, while the goal of increased dietary sodium intake is to expand plasma volume, this may not always occur. Further work is needed to assess the effects of sodium intake on plasma volume expansion, and whether this varies by baseline sodium intake.
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 177 (2013) 72–73
These data do raise the question as to whether salt supplementation should be recommended in POTS patients who already consume at least a moderate degree of sodium. The study should be considered hypothesis generating, and this question needs to be addressed further in a prospective study.
Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: A prospective, randomized, placebo-controlled, doubleblind, crossover evaluation. Cappato R, Castelvecchio S, Ricci C, Bianco E, Vitali-Serdoz L, Gnecchi-Ruscone T, Pittalis M, De Ambroggi L, Baruscotti M, Gaeta M, Furlanello F, Di Francesco D, Lupo PP. (Milan, Italy) J Am Coll Cardiol. 2012; 60: 1323–1329 Article summary The purpose of this study was to investigate the role of ivabradine in the treatment of symptomatic inappropriate sinus tachycardia (IST) using a double-blind, placebo-controlled, crossover design. Due to its I(f) blocking properties, ivabradine can selectively attenuate the high discharge rate from sinus node cells that cause IST. Twenty-one patients were randomized to receive placebo (n = 10) or ivabradine 5 mg twice daily (n = 11) for 6 weeks. After a washout period, patients crossed over for an additional 6 weeks. Each patient underwent symptom evaluation and heart rate assessment at the start and finish of each phase. After taking ivabradine, patients reported elimination of N70% of symptoms (relative risk: 0.25; 95% CI: 0.18 to 0.34; p b 0.001), with 47% of them experiencing complete symptom elimination. These effects were associated with a significant reduction of heart rate at rest (from 88 ± 11 beats/min to 76 ± 11 beats/min, p = 0.011), on standing (from 108 ± 12 beats/min to 92 ± 11 beats/min, p b 0.0001), during 24 h (from 88 ± 5 beats/min to 77 ± 9 beats/min, p = 0.001), and during effort (from 176 ± 17 beats/min to 158 ± 16 beats/min, p = 0.001). Ivabradine administration was also associated with a significant increase in exercise performance. No cardiovascular side effects were observed in any patients while taking ivabradine. The authors concluded that in this cohort, ivabradine significantly improved symptoms associated with inappropriate sinus tachycardia and completely eliminated them in approximately half of the patients, and that ivabradine may be an important agent for improving symptoms in patients with IST. Commentary Patients with both IST and postural tachycardia syndrome (POTS) can be very difficult to treat with pharmacological therapy. Many studies
73
have looked at different approaches to heart rate control in these patients, including with aggressive approaches such as radiofrequency sinus node modification procedures to decrease the sinus node rate. Unfortunately, in many of these cases, patients remain very symptomatic despite a lower heart rate. Many patients with both IST & POTS will report intolerance to rate control medications such as beta blockers at more than minimal doses. It is for this reason that the study from Cappato et al. in patients with IST is so exciting. Ivabradine is a drug in a relatively new class that inhibits the “funny channel”. The funny channel is an ion channel in the pacemaker tissue of the sinus node. It helps to modulate the rate of “phase 4 depolarization” which helps to determine the intrinsic pacing rate. It is currently available in Europe (and much of the world), but not in the United States. In this carefully designed study, 21 patients with IST (and potentially POTS based on the inclusion criteria) were randomized in a crossover fashion to receive placebo or ivabradine twice daily for 6 weeks, a washout phase, and then crossed over to the alternate therapy. The patients were assessed with both a Holter monitor (to assess their heart rate response) and a symptom evaluation at the beginning and end of each phase. Impressively, the authors were able to demonstrate both a heart rate reduction as well as a marked symptom reduction in these patients. Almost 50% of patients reported complete elimination of symptoms related to IST, with an overall 70% reduction in symptom burden. Exercise tolerance also improved during therapy with ivabradine. Early studies with ivabradine suggested possible off target side effects including visual disturbances. Happily, these were not noted in the study. While this study was small, it was conducted in a rigorous manner. These data are very exciting and offer a potential therapy for this patient population that is very difficult to treat. It is noteworthy that in this study there were some patients who experienced the expected heart rate reductions with ivabradine, but continued to have significant symptoms. These findings point to the fact that the cause of symptoms in both POTS and IST are complex. While there is clearly a relationship to heart rate, there are other factors that can drive the symptoms. These data support for the strategy of heart rate control in this patient population. A future comparative effectiveness study of ivabradine versus a beta blocker would be clinically very meaningful. If ivabradine is available to prescribe, then it should certainly be considered for use in this patient population. Those of us who practice in the United States can only hope it will someday receive FDA regulatory approval for use in our patients.
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Highlights in clinical autonomic neurosciences: Treatment insights for postural tachycardia syndrome and inappropriate sinus tachycardia Prepared by: Satish R. Raj ⁎ Autonomic Dysfunction Center, Departments of Medicine & Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
Section Editor: Roy Freeman Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA
This clinical update will focus on articles about the treatment for disorders of sinus tachycardia. The first article assesses the utility of urinary sodium excretion to predict response to dietary sodium intake in patients with postural tachycardia syndrome. The second article is a well-conducted clinical trial of ivabradine for inappropriate sinus tachycardia.
Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome. Zhang Q, Liao Y, Tang C, Du J, Jin H. (Beijing, China) J Pediatr. 2012; 161: 281−284
Article summary The authors sought to investigate whether 24-hour urinary sodium excretion could be an indicator of the effectiveness of salt supplementation in children with postural tachycardia syndrome (POTS). The patient group comprised 30 children with POTS, and the control group comprised 10 healthy children. Serum sodium and 24-hour urinary sodium excretion were measured in all children, and the relationship between 24-hour urinary sodium and symptom severity was analyzed in the 30 patients. At 1 month after initiation of salt supplementation, the receiver operating characteristic curve was used to explore the probability of correctly discriminating responders to salt supplementation from nonresponders using 24-hour urinary sodium excretion as an indicator. Patients with POTS had lower 24-hour urinary sodium excretion than controls (P = 0.022). Symptom severity was negatively correlated with 24-hour urinary sodium excretion (OR, − 0.754; P b 0.001). The receiver operating characteristic curve demonstrated a sensitivity of 77% and specificity of 93% for correct prediction of responders and nonresponders to salt supplementation when a 24-hour urinary sodium excretion of 124 mmol/24 h was used as the cutoff value.
⁎ AA3228 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2195, USA. Tel.: +1 615 343 6499; fax: +1 615 343 8649. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2013.06.008
Commentary POTS is a disorder in which many patients have been found to be hypovolemic. Even without that formal determination in an individual patient, standard medical therapy involves advising patients to augment their dietary sodium intake. This has been done absent significant evidence that sodium intake expands the plasma volume in these patients. Of note, salt supplementation runs counter to the population health advice of the American Heart Association, which has been working for many years to decrease societal dietary sodium intake. This study from Beijing has attempted to address this void. The authors studied 30 children with POTS and 10 healthy children. Each subject underwent a 24-hour assessment of urinary sodium excretion, and an assessment of symptom severity using a simple, custom grading system. Salt supplementation (5–7 g/day) was then initiated and the response was assessed 30 days later in the POTS patients. Not surprisingly, POTS patients had lower urinary sodium excretion than the healthy control subjects. Further, there was an inverse correlation between the severity of orthostatic symptoms and 24-hour urinary sodium excretion. With minor variations, if the patient is following a stable diet then the 24-hour urinary sodium excretion likely reflects the sodium intake over the day. Therefore, these data can be interpreted as stating that POTS patients with a lower dietary sodium intake had worse symptoms than those patients with higher dietary sodium intake. When given a relatively fixed amount of salt supplementation, those patients with a lower baseline sodium excretion (and presumably lower sodium intake) improved significantly. On the other hand, those patients with a higher sodium excretion (N 124 mmol/day) did not respond as well to further supplementation with sodium. Intuitively, those patients who follow a very sodium restricted diet and have orthostatic symptoms improve when their sodium restriction is eased by consuming more dietary salt. These data also suggest that the benefits of sodium supplementation may not extend to all of our patients, specifically, that those patients who already consume a moderate amount of sodium (N 124 mmol/day) do not benefit from further supplementation. Importantly, while the goal of increased dietary sodium intake is to expand plasma volume, this may not always occur. Further work is needed to assess the effects of sodium intake on plasma volume expansion, and whether this varies by baseline sodium intake.
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 177 (2013) 72–73
These data do raise the question as to whether salt supplementation should be recommended in POTS patients who already consume at least a moderate degree of sodium. The study should be considered hypothesis generating, and this question needs to be addressed further in a prospective study.
Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: A prospective, randomized, placebo-controlled, doubleblind, crossover evaluation. Cappato R, Castelvecchio S, Ricci C, Bianco E, Vitali-Serdoz L, Gnecchi-Ruscone T, Pittalis M, De Ambroggi L, Baruscotti M, Gaeta M, Furlanello F, Di Francesco D, Lupo PP. (Milan, Italy) J Am Coll Cardiol. 2012; 60: 1323–1329 Article summary The purpose of this study was to investigate the role of ivabradine in the treatment of symptomatic inappropriate sinus tachycardia (IST) using a double-blind, placebo-controlled, crossover design. Due to its I(f) blocking properties, ivabradine can selectively attenuate the high discharge rate from sinus node cells that cause IST. Twenty-one patients were randomized to receive placebo (n = 10) or ivabradine 5 mg twice daily (n = 11) for 6 weeks. After a washout period, patients crossed over for an additional 6 weeks. Each patient underwent symptom evaluation and heart rate assessment at the start and finish of each phase. After taking ivabradine, patients reported elimination of N70% of symptoms (relative risk: 0.25; 95% CI: 0.18 to 0.34; p b 0.001), with 47% of them experiencing complete symptom elimination. These effects were associated with a significant reduction of heart rate at rest (from 88 ± 11 beats/min to 76 ± 11 beats/min, p = 0.011), on standing (from 108 ± 12 beats/min to 92 ± 11 beats/min, p b 0.0001), during 24 h (from 88 ± 5 beats/min to 77 ± 9 beats/min, p = 0.001), and during effort (from 176 ± 17 beats/min to 158 ± 16 beats/min, p = 0.001). Ivabradine administration was also associated with a significant increase in exercise performance. No cardiovascular side effects were observed in any patients while taking ivabradine. The authors concluded that in this cohort, ivabradine significantly improved symptoms associated with inappropriate sinus tachycardia and completely eliminated them in approximately half of the patients, and that ivabradine may be an important agent for improving symptoms in patients with IST. Commentary Patients with both IST and postural tachycardia syndrome (POTS) can be very difficult to treat with pharmacological therapy. Many studies
73
have looked at different approaches to heart rate control in these patients, including with aggressive approaches such as radiofrequency sinus node modification procedures to decrease the sinus node rate. Unfortunately, in many of these cases, patients remain very symptomatic despite a lower heart rate. Many patients with both IST & POTS will report intolerance to rate control medications such as beta blockers at more than minimal doses. It is for this reason that the study from Cappato et al. in patients with IST is so exciting. Ivabradine is a drug in a relatively new class that inhibits the “funny channel”. The funny channel is an ion channel in the pacemaker tissue of the sinus node. It helps to modulate the rate of “phase 4 depolarization” which helps to determine the intrinsic pacing rate. It is currently available in Europe (and much of the world), but not in the United States. In this carefully designed study, 21 patients with IST (and potentially POTS based on the inclusion criteria) were randomized in a crossover fashion to receive placebo or ivabradine twice daily for 6 weeks, a washout phase, and then crossed over to the alternate therapy. The patients were assessed with both a Holter monitor (to assess their heart rate response) and a symptom evaluation at the beginning and end of each phase. Impressively, the authors were able to demonstrate both a heart rate reduction as well as a marked symptom reduction in these patients. Almost 50% of patients reported complete elimination of symptoms related to IST, with an overall 70% reduction in symptom burden. Exercise tolerance also improved during therapy with ivabradine. Early studies with ivabradine suggested possible off target side effects including visual disturbances. Happily, these were not noted in the study. While this study was small, it was conducted in a rigorous manner. These data are very exciting and offer a potential therapy for this patient population that is very difficult to treat. It is noteworthy that in this study there were some patients who experienced the expected heart rate reductions with ivabradine, but continued to have significant symptoms. These findings point to the fact that the cause of symptoms in both POTS and IST are complex. While there is clearly a relationship to heart rate, there are other factors that can drive the symptoms. These data support for the strategy of heart rate control in this patient population. A future comparative effectiveness study of ivabradine versus a beta blocker would be clinically very meaningful. If ivabradine is available to prescribe, then it should certainly be considered for use in this patient population. Those of us who practice in the United States can only hope it will someday receive FDA regulatory approval for use in our patients.