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The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.

Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, bupropion exteneded release compared with baseline (13.0 vs 21.4 beats/min; P = .001).

“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told theheart.org | Medscape Cardiology.

Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”

POTS patients are mostly healthy, active young women, who after some inciting event — such as viral infection, trauma, or surgery — experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.

A COVID Connection?

The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Taub, from the University of California, San Diego.

“We’re seeing an incredible number of patients post-COVID that meet the criteria for POTS and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine, have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”

Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols but, mechanistically, whether it’s POTS from COVID or from another type of infection — like Lyme disease or some other viral syndrome — it should work the same, Taub said. “POTS is POTS.”

There are no first-line drugs for POTS and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta blockers, also lower blood pressure and can aggravate depression and fatigue.

Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and also has a second class IIb recommendation for inappropriate sinus tachycardia.

The present study, reported in the February 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.

A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, and then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5 mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits, in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.

Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.

Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (= .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1000 pg/mL) than in those with lower NE levels (600 to 1000 pg/mL).

“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?'”

Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary, Alberta, Canada, said in an interview.

In a related editorial, however, Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”

Asked about the point, Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”

Both Raj and Taub said they expect the results will be included in the next scientific statement for POTS but, in the meantime, it may be a struggle to get the drug covered by insurance.  

“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.

Another question going forward, he said, is whether ivabradine is superior to beta blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary and about to launch. The primary completion date is set for 2024.

The study was supported by a grant from Amgen. 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 National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.

J Am Coll Cardiol. 2021;77;861-871, 872-874. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook.

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