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Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

Original Investigation

J Am Coll Cardiol, 77 (7) 861–871
Sections

Central Illustration

Abstract

Background

Postural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited.

Objectives

This study investigated the effect of ivabradine (selective blocker of the Ifunny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test.

Methods

In total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.

Results

The average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.

Conclusion

Ivabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.

Introduction

Postural orthostatic tachycardia syndrome (POTS) is a poorly understood, complex multisystem clinical disorder that predominantly affects women. The majority of these patients are young, Caucasian women (1,2), and current prevalence estimates range from 500,000 to 3 million patients nationwide (2). Patients with POTS experience a wide spectrum of debilitating symptoms (2–4). Upon assuming a standing position from a supine position, patients have an increase in heart rate by 30 beats/min. This is often accompanied by lightheadedness, palpitations, dyspnea, headaches, and near-syncope (3–8). This positional elevation in heart rate causes extreme fatigue and weakness, which impairs their ability to remain upright and perform daily tasks. Ultimately, this reduces a patient’s functional status and quality of life (QOL). These symptoms may improve when patients return to a recumbent position (2). Unfortunately, many patients become bedridden due to the limited efficacy of current therapies.

POTS is currently understood to be composed of 5 subtypes: 1) hyperadrenergic; 2) neuropathic; 3) hypovolemic; 4) joint-hypermobility-related; and 5) immune-related. However, these subtypes are not mutually exclusive, as symptoms and treatments often overlap. The hyperadrenergic subtype, which comprises up to 50% of POTS (5), is characterized by abnormal sympathetic nervous system activation. The body is in a constant “flight or fight” mode, which results in abnormal responses including elevated heart rate and decreased perfusion of organs. For the hyperadrenergic subtype, supine and standing plasma norepinephrine (NE) levels are markedly elevated compared with healthy patients. In healthy patients, supine plasma NE has been reported to be approximately 200 pg/ml and doubles to 400 to 500 pg/ml upon standing (9–11). In patients with POTS, however, NE levels can triple or quadruple upon standing (405 to 1,207 pg/ml) (2,10,11).

There are currently no Class I recommendations for the treatment of POTS (3,5,12). Ivabradine has a unique and selective mechanism of action, which specifically blocks the Ifunny channel of the sinoatrial (SA) node, consequently lowering heart rate directly without lowering blood pressure (BP). The SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) study showed that ivabradine reduces heart failure hospitalizations by lowering heart rate (13). The SHIFT trial investigators hypothesized that isolated heart rate reduction without BP lowering with ivabradine unloads the left ventricle and reverses adverse cardiac remodeling that contributes to heart failure (14). In the United States, ivabradine is approved by the U.S. Food and Drug Administration for patients with systolic heart failure with Class IIa recommendation to reduce heart failure hospitalizations (15,16). Although ivabradine has a Class IIa recommendation for inappropriate sinus tachycardia, it is not included in the current guidelines for POTS (5).

Ivabradine may be particularly useful in patients with a component of hyperadrenergic POTS by selectively inhibiting the SA node and decreasing heart rate. Many prior small studies and case reports (17–29) have shown the promising potential of ivabradine for POTS. We have conducted the first randomized, double-blinded, placebo-controlled, crossover trial in which patients with hyperadrenergic POTS as the predominant subtype were started on ivabradine and compared with placebo.

Methods

This clinical study was approved by the University of California, San Diego Institutional Review Board and registered on ClinicalTrials.gov ( NCT03182725). All patients provided informed written consent.

Definitions

POTS is a clinical disorder classified by: 1) symptoms upon standing such as lightheadedness, palpitations, tremors, weakness, blurry vision, and fatigue; 2) increase in heart rate ≥30 beats/min upon postural change from recumbent to upright position within 10 min of standing; and 3) absence of orthostatic hypotension (3,5,8,30). Hyperadrenergic POTS, a subtype of POTS, is defined as an elevation in NE >600 pg/ml upon standing and a systolic BP increase of >10 mm Hg when standing upright for 10 min (5). We did not use the systolic BP criteria, as we recognized clinically that many patients had overlapping subtypes (e.g., hyperadrenergic and hypovolemic that resulted in lack of systolic BP increase). A positive head-up tilt table test (HUTT) (heart rate ≥30 beats/min) and NE (≥600 pg/ml) were required for study enrollment.

Study design

The study design is presented in Figure 1. Utilizing a randomized, double-blinded, placebo-controlled crossover design, eligible patients with hyperadrenergic POTS were started on either ivabradine or placebo for 1 month, underwent a 1-week washout period and were crossed over to the other treatment for 1 month (Figure 1). Study participation lasted approximately 2.5 months with 7 clinic visits.

Figure 1
Figure 1

Summary of Study Design

There were 7 clinic visits over the course of 2 months. Includes all patients who completed the study (n = 22). HUTT = head-up tilt-table test; NE = norepinephrine; OVM = orthostatic vital monitoring; POTS = postural orthostatic tachycardia syndrome; SF-36 = RAND 36-Item Health Survey 1.0.

Randomization and blinding

All patients who completed the study took both ivabradine and placebo, but at different time points. The order in which they received the treatment, either ivabradine first or placebo first, was randomly assigned with a web-based randomization table provided by the study statistician (S.G.). Both the research team and patients were blinded to the treatment and treatment order. Patients were unblinded upon study completion or withdrawing.

Patient selection

Patients were screened and recruited from University of California, San Diego cardiology clinics from 2018 to 2020. Patients age 18 to 65 years with a diagnosis of hyperadrenergic POTS as defined by baseline standing NE >600 pg/ml (5) and heart rate increase >30 beats/min on HUTT were enrolled. Patients with a resting heart rate <60 beats/min, atrial fibrillation, or supraventricular tachycardia were excluded. Women who were pregnant and/or breastfeeding were excluded. Women of childbearing age were required to use contraception during the study. Patients on medications such as heart rate modulators (beta-blockers, calcium-channel blockers), cholinesterase inhibitors (pyridostigmine), vasoconstrictors (midodrine, octreotide, droxidopa, stimulants), sympatholytics (clonidine, methyldopa), or blood volume increasers (fludrocortisone, desmopressin, salt supplementation) for their POTS symptoms were required to undergo a 1-week washout before their screening visit. Although patients had symptoms of orthostatic intolerance, none of the patients had orthostatic hypotension at enrollment.

Head-up tilt testing

The HUTT was conducted in the mornings with patients fasting for 8 h by study physicians (J.C.H. and P.R.T.) at the baseline visit. Heart rate and BP were monitored continuously. Patients were instructed to report any symptoms. HUTT was abnormal if patients had an increase in heart rate by at least 30 points from baseline, and experienced symptoms of orthostatic intolerance (5,31).

Norepinephrine testing

To obtain plasma NE levels, patients lay in a quiet dark room supine for 15 min. At the end of 15 min, blood was drawn. Then, patients were asked to stand upright for 15 min, at which point blood was drawn again (4,6). Blood was collected in chilled lithium heparin vacuum tubes for the catecholamine panel. Plasma was separated by refrigerated centrifugation and frozen within an hour of collection. Samples were analyzed using quantitative high-performance liquid chromatography. Plasma NE levels were obtained at baseline, end of ivabradine month, and end of placebo month.

Intervention

After randomization, patients were started on a 5-mg twice daily (bid) dose of ivabradine or placebo. In 6 cases, a modified, lower dose of 2.5-mg bid was initiated due to the principal investigator’s (P.R.T.) evaluation of the patient’s orthostatic vitals monitoring (OVM). Patients were instructed to take the medication with meals, once in the morning and once in the evening. After 2 weeks, patients returned for OVM so the principal investigator (P.R.T.) could determine if dose adjustments were needed. To conduct OVM, patients lay supine for at least 3 min to establish a baseline. At the end of 3 min, heart rate and BP were measured. Then, patients stood for at least 3 min; at the end of 3 min, their standing heart rate and BP were measured.

Medication dose was changed according to the patient’s heart rate response and tolerance of current dose. If the resting supine heart rate was >70 beats/min, doses were increased to 7.5 mg bid (or 5 mg bid for patients initiated on a 2.5-mg dose). If the resting supine heart rate was <70 beats/min, there was no increase in dose. All dose titrations were done by the study principal investigator (P.R.T.). At 2 weeks after the initial titration visit, patients returned to the clinic to repeat NE bloodwork and OVM. At this visit, patients stopped the medication and commenced a 1-week washout period. When the washout period ended, they returned to the clinic to initiate the second month of treatment. As part of the crossover design, patients on placebo were switched to ivabradine, and patients on ivabradine were switched to placebo. The previously mentioned protocol was followed for the 2-week titration and end-of-month final visit.

QOL was assessed using the RAND 36-Item Health Survey 1.0 (SF-36) questionnaire upon enrollment in the study (baseline), end of placebo month, and end of ivabradine month. SF-36 questions are subdivided into 8 distinct categories: physical functioning, physical health, emotional problems, vitality, emotional well-being, social functioning, pain, and general health.

Outcomes

The primary outcome was change in heart rate after 1 month on ivabradine. The secondary outcome was a change in self-reported QOL measured by the SF-36 after 1 month of ivabradine. As an exploratory outcome, changes in plasma NE levels were also assessed after 1 month on ivabradine. Heart rate, QOL, and NE were all assessed at 3 time points: baseline, end of placebo month, and end of ivabradine month.

Statistical methods

Descriptive statistics and exploratory graphing, such as frequencies, means, SDs, box and whisker plots, stem and leaf diagrams, and scatter plots, were used to assess the normality of the data in terms of the presence of skew and/or outliers. Furthermore, z-score for skewness and kurtosis were computed for all outcomes. The following variables were skewed: pre-phase (heart rate delta), baseline (physical health, body mass index), placebo phase (ne supine), washout phase (standing systolic), active titration (standing systolic), and active (supine systolic, standing systolic). Log transformation was done to normalize the following outcomes: washout phase (standing systolic), active (supine systolic, standing systolic), and baseline (physical health, body mass index). Final analyses for heart rate and quality of life were repeated using the original data (not log-transformed) and using nonparametric methods with similar results. All reported analyses were performed with the original non–log-transformed data format. The comparability of the baseline values and treatment order were tested with analyses of variance (ANOVAs) for continuous variables or chi-square analyses for dichotomous variables. Data was inspected for bias due to dropouts, missing data, and treatment order. Treatment order/carryover effect was tested using 2 methods. In the first method, treatment order was added as an independent factor to the repeated measures (RM)-ANOVA model, and all interactions were tested. In the second method, the approach by Wellek and Blettner (32) was used. None of the interactions or Student’s t-test values were significant, indicating a lack of any carryover or treatment-order effect. Hypotheses were tested using RM-ANOVA. RM-ANOVA with 2 within factors were used: 1) treatment with 2 levels: placebo and ivabradine; and 2) body position with 2 levels: supine and standing. The body position factor was nested within the treatment factor. RM-ANOVA models with 1 within factor of treatment were used when only 1 position was compared across treatments. Patients were also stratified based on the baseline NE standing position values into 2 groups, high NE (600 to 1,000 pg/ml) and very high NE (≥1,000 pg/ml), and RM-ANOVA was repeated with addition of the NE baseline grouping factor comparing placebo with ivabradine across 2 positions. Treatment effect estimates with corresponding p values were based within patient comparisons. All statistical tests were 2-tailed. All available data was used in analyses, and no patients were excluded due to missing data. SF-36 was scored based on RAND instructions (33). Differences were considered statistically significant if a p value of 0.05 or less was obtained using SPSS version 26 (IBM, Armonk, New York) (34).

Results

Patients

Baseline demographics and characteristics of all patients are shown in Table 1. In total, 37 patients (average age 32.5 ± 11.4 years; n = 35 women) were screened, 10 failed screening (7 did not meet NE criteria, and 3 did not meet criteria for POTS by HUTT), and 1 withdrew prior to randomization. Of the 26 randomized patients, 22 patients completed the study and were included in the final data analysis (Figure 2). Of the 4 patients who withdrew after randomization, 1 dropped out on placebo due to other health concerns, and 3 dropped out while on ivabradine due to nausea and drowsiness after 3 days, fatigue after 21 days, and phosphenes after 4 days. These side-effects were among the typical side-effects associated with ivabradine, such as phosphenes, tiredness, and palpitations (12,35,36). None of our patients experienced any worsening of POTS symptoms. Ivabradine was not stopped by the study investigators due to adverse events in any patient. There were no significant demographic differences between those who dropped out and those who completed the study.

Figure 2
Figure 2

Flowchart Overview of Patients From Screening to Study Completion

A total of 37 patients were screened, 26 patients were randomized, and 22 patients completed the study. POTS = postural orthostatic tachycardia syndrome.

Table 1 Baseline Demographics and Characteristics

Randomized to Placebo First (n = 16)Randomized to Ivabradine First (n = 6)
Age, yrs35.6 ± 10.629.3 ± 14.4
Weight, lbs142.7 ± 38.6142.8 ± 32.4
Body mass index, kg/m224.1 ± 7.122.3 ± 4.7
Sex
Female
Male

15
1

6
0
Race
White
Mixed
Unknown

13
2
1

6
0
0
Ethnicity
Caucasian
European, non-Hispanic
Hispanic
Non-Hispanic
Other, non-Hispanic
Unknown
Unknown, non-Hispanic

1
5
1
3
4
1
1

0
6
0
0
0
0
0
Norepinephrine, pg/ml
Supine
Standing

513.6 ± 149.4
1,143.4 ± 351.7

328.8 ± 96.0
842.3 ± 221.7
Heart rate, beats/min
Supine
Standing

77.4 ± 13.4
101.1 ± 19.0

74.8 ± 14.9
111.2 ± 14.2
Systolic blood pressure, mm Hg
Supine
Standing

121.8 ± 17.2
122.9 ± 24.7

115.8 ± 11.8
117.3 ± 12.5
Diastolic blood pressure, mm Hg
Supine
Standing

78.8 ± 13.8
82.3 ± 16.9

76.2 ± 14.5
78.8 ± 9.9

Values are mean ± SD or n. n = 22 for those who completed the study.

Of the 26 randomized patients, the majority had symptoms for 1 to 3 years prior to the diagnosis of POTS. Thirty percent of patients had a history of unexplained syncope. Also, 5 patients had a diagnosis of anxiety/panic disorder: 3 patients had both anxiety and depression, and 1 had depression.

Dosage

A total of 7 patients started on 2.5 mg bid, 16 on 5 mg bid, and 1 on 5 mg in the morning and 2.5 mg in evening. At their ivabradine titration visit, 1 patient decreased dose from 5 to 2.5 mg bid due to complaints of self-reported bradycardia, and 2 patients’ doses were increased to 7.5 mg bid due to elevated supine and standing heart rate.

Primary outcome: heart rate

The effect of ivabradine on heart rate is shown in Table 2. Ivabradine significantly reduced heart rate upon standing compared with placebo (p < 0.001). We also found that the characteristic positional surge in heart rate from supine to standing was significantly blunted with ivabradine compared to baseline (p = 0.001). No patients experienced symptomatic bradycardia while on ivabradine.

Table 2 The Effect of Ivabradine on Heart Rate

BaselineIvabradinePlacebop ValueCohen’s D95% CI
Supine heart rate, beats/min73.6 ± 11.764.9 ± 6.577.5 ± 12.80.0011.260.706–1.820
Standing heart rate, beats/min95.1 ± 16.877.9 ± 9.394.2 ± 16.20.0011.050.544–1.58
Delta heart rate (standing vs. supine), beats/min21.4 ± 15.313.1 ± 8.617.0 ± 10.40.0010.7530.300–1.250

Ivabradine significantly lowers heart rate compared with placebo (p < 0.001). Ivabradine also significantly decreases the surge in heart rate upon standing (p = 0.001) compared with baseline with a 2-way interaction of treatment and body position. Parameters reported as mean ± SD. p-values compared mean parameters between placebo and ivabradine. n = 22.

CI = confidence interval.

∗ Statistically significant (p < 0.05).

Blood pressure

No clinically significant hypotension was found in patients on ivabradine (Supplemental Table 1). We also found no clinically significant statistical difference in systolic or diastolic BP between placebo and ivabradine, or between postural changes.

Secondary outcome: quality of life

Compared with placebo, significant improvements were seen in QOL measures of physical functioning (p = 0.008) and social functioning (p = 0.021) (Table 3). As expected, there were no significant differences between baseline and placebo.

Table 3 The Effect of Ivabradine on Quality of Life (SF-36)

BaselineIvabradinePlacebop ValueCohen’s D95% CI
Physical functioning41.6 ± 21.953.4 ± 27.044.1 ± 22.40.0080.5700.308–0.894
Physical health13.1 ± 23.538.9 ± 40.026.1 ± 34.30.1590.2230.000–0.575
Emotional problems53.4 ± 45.062.1 ± 43.257.2 ± 44.70.5670.0000.000–0.378
Vitality19.0 ± 16.930.8 ± 24.423.8 ± 20.50.1020.2890.000–0.628
Emotional well-being61.9 ± 16.563.9 ± 17.460.0 ± 18.80.1040.2860.000–0.626
Social functioning43.2 ± 28.756.6 ± 31.143.8 ± 27.30.0210.4770.228–0.800
Pain48.7 ± 33.253.4 ± 30.949.2 ± 30.70.2320.1460.000–0.525
General health33.5 ± 18.533.1 ± 19.332.7 ± 18.20.8970.0000.000–0.046

Values are mean ± SD. While on ivabradine, significant improvements were observed in physical functioning (p = 0.008) and social functioning (p = 0.021) compared with placebo. The p values compared mean parameters between placebo and ivabradine. n = 22.

CI = confidence interval; SF-36 = RAND 36-Item Health Survey 1.0.

∗ Statistically significant (p < 0.05).

Exploratory outcomes

Norepinephrine levels

Ivabradine did not lower supine NE level (p = 0.316) or the standing NE level (p = 0.076) (Table 4). There was a strong trend for the decrease in NE levels from supine to standing for ivabradine compared with placebo (p = 0.056). We did note a significant reduction (p = 0.030) in NE levels from supine to standing on ivabradine (442.3 ± 232.6 pg/ml) compared with baseline (598.1 ± 316.2 pg/ml).

Table 4 The Effect of Ivabradine on NE Levels

BaselineIvabradinePlacebop ValueCohen’s D95% CI
Supine NE, pg/ml459.43 ± 161.7472.0 ± 219.3523.4 ± 223.00.3160.04930.000–0.625
Standing NE, pg/ml1,046.0 ± 346.5914.3 ± 358.51,055.4 ± 371.20.0760.3370.000–0.829
Delta NE (standing vs. supine), pg/ml598.1 ± 316.2442.3 ± 232.6532.1 ± 259.00.056
0.030
0.3770.000–0.866

Values are mean ± SD. There was a strong trend in the reduction of plasma NE upon standing with ivabradine compared with placebo (p = 0.056). Ivabradine significantly decreased the change in NE from supine to standing (p = 0.030) compared with baseline with a 2-way interaction of treatment and body position. The p values compared mean parameters between placebo and ivabradine. n = 22 for supine NE; n = 21 for standing NE and delta NE due to laboratory error.

CI = confidence interval; NE = norepinephrine.

∗ Statistically significant (p < 0.05).

Stratification of NE level on effect of ivabradine

When baseline (before study enrollment) standing NE was stratified into high NE (600 to 1,000 pg/ml) and very high NE (≥1,000 pg/ml), 11 patients were in the high NE and 10 patients in the very high NE group (Table 5). Those in the very high NE group had a greater magnitude of reduction in standing NE with ivabradine compared with those in the high NE group (p = 0.026) (Central Illustration).

Table 5 Stratification by Baseline Standing Norepinephrine Levels (pg/ml)

PlaceboIvabradinep ValueCohen’s D95% CI
High NE supine, pg/ml503.5 ± 299.3433.7 ± 240.10.7400.0000.000–0.403
Very high NE supine, pg/ml545.3 ± 100.0514.1 ± 197.6
High NE standing, pg/ml872.0 ± 352.4803.6 ± 373.70.3250.0320.000–0.581
Very high NE standing, pg/ml1,257.2 ± 286.01,036.1 ± 314.7
Delta (Standing vs. supine) in high NE, pg/ml368.5 ± 171.2369.9 ± 188.90.0260.4770.127–0.904
Delta (Standing vs. supine) in very high NE, pg/ml711.9 ± 218.9522.0 ± 259.0

Values are mean ± SD. Upon stratifying NE levels based on standing NE levels prior to study enrollment, those in the very high NE (≥1,000 pg/ml) had a greater reduction in standing NE with ivabradine compared with those in the high NE group (600 to 1,000 pg/ml) (p = 0.026). The p values compared mean parameters between placebo and ivabradine. n = 11 in high NE, n = 10 in very high NE.

CI = confidence interval; NE = norepinephrine.

∗ Statistically significant (p < 0.05).

Central Illustration
Central Illustration

Ivabradine Improves Heart Rate, Quality of Life, and Norepinephrine Levels in Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

Patients with hyperadrenergic postural orthostatic tachycardia syndrome (POTS) experience severe tachycardia with symptoms of orthostatic intolerance upon standing and have a reduced QOL. After 1 month of ivabradine, patients exhibited significant improvements in heart rate and QOL. Our findings illustrate the clinical impact of ivabradine as a safe and effective treatment option for patients with hyperadrenergic POTS.

Treatment order/carryover effect

Two different methods were used to examine the treatment order/carryover effect (see the Statistical Methods section). When treatment order was added to the RM-ANOVA model as an independent factor, none of the interactions of treatment order were significant (Supplemental Table 2). Similarly, none of the Student’s t-test values were significant. These analyses indicated no carryover or treatment order effect.

Discussion

To date, this is the first study of its kind, to the best of our knowledge, to investigate the effects of ivabradine in patients with hyperadrenergic POTS as the predominant subtype in a randomized, double-blinded, placebo-controlled, crossover trial. We show that ivabradine is safe and effective in lowering the heart rate of patients with hyperadrenergic POTS and improves QOL.

There are currently no Class I pharmacological recommendations for POTS, and the current recommendations for POTS, such as midodrine and fludrocortisone, are Class IIb recommendations (5,12). Additionally, medications used to lower heart rate, such as beta-blockers and calcium-channel blockers concurrently lower BP, which can limit their use. Ivabradine is a specific cardioselective agent that inhibits the Ifunny channel of the SA node and lowers heart rate directly without lowering BP. Similar to the SHIFT trial, which showed 15-point mean heart rate reduction with ivabradine in patients with heart failure (13), we saw a 13-point mean heart rate reduction in patients with hyperadrenergic POTS.

This study showed that patients who were treated with ivabradine had lower heart rate during treatment compared with when they were taking placebo (p < 0.001). Additionally, the typical surge in heart rate that occurs in patients with POTS upon standing was also significantly blunted with ivabradine compared with baseline (p = 0.001). Moreover, these significant reductions in heart rate with ivabradine were also associated with improvements in QOL and NE levels, which had not been demonstrated with prior studies.

According to the SHIFT trial with systolic heart failure patients, the magnitude in heart rate reduction with ivabradine depended on the baseline heart rate (13). Patients with POTS in this study experienced a lower heart rate upon standing while on ivabradine (77.9 ± 9.3 beats/min) versus placebo (94.2 ± 16.2 beats/min). When we examined the change in heart rate that occurs from supine to standing, patients who were on ivabradine had a smaller rise in heart rate (13.1 ± 8.6 beats/min). These reductions in heart rate both in a standing position and when changing positions are within previously reported ranges (11 to 17 beats/min) (26,28,29,35). The improvement in heart rate with a therapeutic dose range of 5 to 15 mg/day is also similar to prior studies (26–29,35). Only 1 (4.5%) patient in our study reported phosphenes, which is also similar to the reported range of 4.5% to 18% (27–29). As expected, there were no clinically significant differences in BP when ivabradine was compared with baseline or placebo.

Prior studies examining the effect of ivabradine in POTS patients were not randomized and did not selectively enroll the hyperadrenergic POTS subtype. Ruzieh et al. (29) showed significant reductions in standing heart rate on ivabradine (95.1 ± 13.7 beats/min) compared with baseline (107.4 ± 14.1 beats/min) in 49 patients with POTS. However, this was a retrospective cohort study over 3 to 12 months without QOL assessment (29,35). Similarly, Delle Donne et al. (28) showed significant decreases in resting heart rate with ivabradine (71.3 ± 16.5 beats/min) compared with baseline (82.5 ± 13.6 beats/min) in a retrospective cohort study with 22 POTS patients over 1 to 17 months, but without assessing QOL (28,35). In a retrospective cohort study conducted by McDonald et al. (27) over 2 to 29 months with 20 POTS patients, symptom improvement was reported with ivabradine (utilizing a study-specific assessment tool), but the magnitude of heart rate reduction was not quantified (27,35). Although Barzilai and Jacob (26) showed the benefit of ivabradine in 8 patients with POTS, this was a prospective open-label study with only a single dose of ivabradine administration (26,35).

The secondary outcome of this study was the effect of ivabradine on QOL. The severe tachycardia patients with POTS experience limits their functional status, as they are unable to remain upright or walk for long periods of time. It has been reported that over 25% of patients with POTS are unable to work (6,37). In addition to the reduced QOL, many patients have concomitant depression and anxiety (37–43). Patients with POTS often have many other comorbidities and are on multiple medications with numerous side-effects, which may further decrease QOL. In our study with 22 POTS patients, there were statistically significant improvements in QOL measures. Compared with placebo, patients reported significant improvements in physical functioning (p = 0.008) and social functioning (p = 0.021). This improvement in QOL is remarkable because this was achieved with ivabradine alone, and patients were not on other medications for POTS. Even though prior studies with ivabradine did not assess QOL, Moon et al. (44) did show improvements in QOL with beta-blockers. However, beta-blockers alone showed improvement in the physical components of SF-36, and the addition of pyridostigmine was needed to improve the mental component of SF-36 (44). In our study with ivabradine alone, we noted improvements in both the physical and mental components of SF-36. This further reinforces the improved QOL patients experienced with ivabradine.

Furthermore, based on our review of the published data, plasma NE levels were not examined with prior ivabradine studies (17–29). Although plasma NE levels were reported with clonidine administration in dysautonomia, it was not statistically significant (45). This is the first study to demonstrate statistically significant improvements with postural changes in heart rate and a strong trend toward improving plasma NE upon standing with ivabradine in patients with hyperadrenergic POTS as the predominant subtype. The reduction in plasma NE levels with ivabradine between supine and standing positions was nearly significant compared with placebo (p = 0.056). Clinically, patients are most symptomatic when changing positions, and we have shown significant reductions in NE levels upon standing with ivabradine (p = 0.030). Moreover, this study shows that patients with standing plasma NE levels ≥1,000 pg/ml at baseline had a larger magnitude of reduction in NE levels with ivabradine than those with baseline standing NE levels 600 to 1,000 pg/ml (p = 0.026). Since POTS is a heterogenous disorder with overlapping subtypes, stratification by plasma NE levels could potentially be a clinically useful tool in determining which patients will derive the most benefit from ivabradine.

Due to its heart rate reduction without lowering BP, and possible down-regulation of the sympathetic nervous system as evidenced by lower NE levels, ivabradine has clinical benefit in patients with hyperadrenergic POTS as the predominant subtype. Ivabradine may also provide an additional benefit if combined with other pharmacological agents. Further research is warranted for the use of ivabradine in other subtypes of POTS.

Study limitations

One potential limitation of this study is the small sample size; however, a small study sample would be susceptible to false-negative (type II) error, whereas we found several statistically significant results. Another limitation is that although the study investigators and patients were blinded to the intervention, many patients noticed significant differences and suspected that they were on ivabradine. Additionally, patients were only on 1 month of ivabradine, and a longer study duration may be warranted to assess potential long-term effects.

Conclusions

POTS is a debilitating multifactorial clinical disorder with complex pathophysiology that significantly impairs QOL for patients. This study shows that ivabradine provides notable improvements in heart rate, QOL, and NE in patients with hyperadrenergic POTS.

Perspectives

COMPETENCY IN MEDICAL KNOWLEDGE: Ivabradine selectively inhibits sinoatrial node automaticity, decreasing heart rate without lowering BP. In patients with hyperadrenergic POTS, this alleviates symptoms and improves QOL.

TRANSLATIONAL OUTLOOK: Larger and longer-term studies are needed to identify the underlying causes of hyperadrenergic POTS; assess the durability of the ivabradine treatment effect; and define optimum timing, intensity, and duration of therapy.

Funding Support and Author Disclosures

A grant from Amgen was received to conduct this investigator-initiated clinical trial. No financial support was received in the writing of this paper. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the NIH (R01 DK118278-01 and R01 HL136407), the American Heart Association (SDG #15SDG2233005), and the Department of Homeland Security/FEMA (EMW-2016-FP-00788). Dr. Hsu has served as a consultant for Medtronic, Abbott, Boston Scientific, Biotronik, Biosense Webster, Zoll Medical, Pfizer, Bristol Myers Squibb, and Janssen Pharmaceuticals; has received research grants from Biosense Webster and Biotronik; and is a shareholder in Acutus Medical and Vektor Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

BP

blood pressure

HUTT

head-up tilt table test

NE

norepinephrine

OVM

orthostatic vitals monitoring

POTS

postural orthostatic tachycardia syndrome

QOL

quality of life

SA

sinoatrial node

SF-36

RAND 36-Item Health Survey 1.0

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Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

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