By Michael H. Crawford, MD, Editor

SYNOPSIS: A study of ivabradine in patients with the common hyperadrenergic subtype of the postural orthostatic tachycardia syndrome led to slower standing heart rates, lower plasma norepinephrine levels, and improved quality of life after one month.

SOURCE: Taub PR, Zadourian BS, Lo HC, et al. Randomized trial of ivabradine in patients with hyperadrenergic postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2021;77:861-871.

Most patients with postural orthostatic tachycardia syndrome (POTS) carry the hyperadrenergic variety, for which there are no class I therapies. Ivabradine, a selective sinus node inhibitor, has shown promise for this condition. Taub et al conducted the first randomized, double-blind, placebo-controlled, crossover trial of ivabradine compared to placebo.

Patients with clinically diagnosed POTS who recorded a heart rate > 30 beats/minute (bpm) with head-up tilt table test (HUT) and upright plasma norepinephrine (NE) levels > 600 pg/mL were candidates for the study. Patients with resting heart rates < 60 bpm, atrial fibrillation, supraventricular tachycardia, or orthostatic hypotension were excluded, as were women who were pregnant or breast feeding. All treatments for POTS ended one week before the screening visit and throughout the trial. Researchers drew blood for NE levels after 15 minutes of supine rest and then after 15 minutes of standing. Accepted subjects were randomized to 5 mg twice-daily of ivabradine or placebo. The dose was adjusted after two weeks based on the heart rate response to three minutes of standing. Two weeks later, vital signs and plasma NE were repeated, therapy (ivabradine or placebo) ended for one week, and patients switched to the opposite therapy, with a titration visit at two weeks and a final visit at four weeks. Quality of life (QOL) was assessed at baseline, at the end of the first month, and at the end of the second month of therapy. The primary outcome was the change in heart rate after one month of ivabradine. Secondary outcomes included QOL and plasma NE levels.

After evaluating 37 potential subjects, 26 were randomized. Four patients withdrew from the study after randomization (one on placebo for other health reasons and three on ivabradine who experienced adverse effects, such as nausea, drowsiness, fatigue, and phosphenes). Of the 22 patients who completed the study, 21 were women and 19 were white.

Supine heart rate was lower on ivabradine (65 bpm vs. 74 bpm; P < 0.001), as was standing heart rate (78 bpm vs. 95 bpm; P < 0.001). There were no significant changes in supine or standing blood pressure readings on ivabradine. QOL was significantly better on ivabradine in the physical (P = 0.008) and social (P = 0.02) functioning domains. Ivabradine cut the difference between supine and standing plasma NE levels (442 pg/mL compared to 598 pg/mL for placebo; P = 0.03), with the greatest differences noted in those with the highest baseline standing NE levels. The authors concluded ivabradine slows standing heart rate, lowers plasma NE levels, and improves QOL in patients with hyperadrenergic POTS.

COMMENTARY

POTS is a heterogeneous disorder with recognized subtypes: hyperadrenergic (the most common), neuropathic, and hypovolemic. It also can be associated with joint hypermobility disorders (e.g., Ehlers-Danlos) and immunologic disorders. Significant overlap between these subgroups often is present as well. The definition of POTS involves three characteristics: symptoms of orthostatic intolerance and tachycardia, an acceleration in standing heart rate > 30 bpm, and no orthostatic blood pressure changes. Standing plasma NE levels > 600 pg/mL and a supine to standing blood pressure rise of more than 10 mmHg further characterize the hyperadrenergic subtype. Taub et al ignored the blood pressure criterion because they recognized a frequent overlap between the hyperadrenergic subtype and the hypovolemic subtype.

POTS is almost exclusively seen in white women of reproductive age and often is perceived as precipitated by viral infections, concussion, surgery, pregnancy, or the onset of puberty. It is not a mortal condition but causes considerable morbidity, such that patients cannot function well upright and can become depressed, anxious, and occasionally bedridden. It is estimated to afflict 1 to 3 million women in the United States. The condition could be genetic, as researchers have observed it in families and those with hypermobility disorders. Usually, POTS is self-limited, but may take years to resolve or become a chronic condition in a few.

Generally, diagnosis is clinical, with few requiring HUT or other tests. However, Taub et al raised the possibility that plasma NE levels may be useful to identify the hyperadrenergic subtype. Therapy is driven by symptoms and signs of the disease. The only guideline class I recommendations are exercise training, preferably swimming or rowing, and IV saline for acute decompensations.1 All the pharmacologic agents are class IIb. Fludrocortisone can be given to increase plasma volume. Non-selective beta-blockers, such as propranolol, can be useful to blunt tachycardia. However, hypotension limits this approach. Vasoconstrictors, such as midodrine, can be helpful in those with mixed orthostatic features. Finally, sympatholytic agents, such as alpha-methyldopa or clonidine, can be tried, but side effects limit these agents.

Anecdotally, ivabradine has shown promise, but Taub et al were the first to seriously study its use. The results show significant reductions in standing heart rate and improvements in QOL. However, this was a small trial of rather chronic POTS patients, with an average standing heart rate of 95 bpm. One could argue these were mild cases. Also, it is difficult to blind a study when the drug lowers heart rate. In addition, this was a short trial (one month on treatment). Finally, the authors did not compare ivabradine to other recognized treatments. There is a trial in progress comparing ivabradine to propranolol, which should shed more light on the matter when finished. At this time, it seems reasonable to try ivabradine in patients who present with hyperadrenergic POTS and have not responded well to other therapies. 

REFERENCE

  1. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015;12:e41-e63.