Heart Failure Drug Tempers Heart Rate, Symptoms in POTS

Ivabradine (Corlanor) appeared safe and effective for the hyperadrenergic subtype of postural orthostatic tachycardia syndrome (POTS) in a small, randomized, crossover trial.

In the 22-person study, individuals randomized to ivabradine instead of placebo were associated with:

• Significantly reduced supine heart rate (64.9 vs 77.5 beats/min, P=0.001) and standing heart rate (77.9 vs 94.2 beats/min, P=0.001)
• Significantly improved quality of life per SF-36 physical functioning (53.4 vs 44.1 points, P=0.008) and social functioning domains (56.6 vs 43.8 points, P=0.021)
• Numerical trend of smaller change in plasma norepinephrine from supine to standing positions (difference of 442.3 vs 532.1 pg/mL, P=0.056)

There were no cases of symptomatic bradycardia or clinically significant hypotension when patients were on ivabradine, reported Pam Taub, MD, of the University of California, San Diego in La Jolla, and colleagues.

“Due to its heart rate reduction without lowering BP [blood pressure], and possible down-regulation of the sympathetic nervous system as evidenced by lower norepinephrine levels, ivabradine has clinical benefit in patients with hyperadrenergic POTS as the predominant subtype,” they wrote in the Journal of the American College of Cardiology.

Ivabradine was FDA approved in 2015 for people with heart failure and elevated heart rate. The drug works by specifically blocking the I_funny channel of the sinoatrial node, thereby lowering heart rate directly without lowering BP — an important advantage over beta-blocker therapy.

The idea that reduced orthostatic increase in plasma norepinephrine might reflect an ivabradine-mediated down-regulation of the sympathetic nervous system “is unprecedented to our knowledge,” commented Satish Raj, MD, MSCI, and Robert Sheldon, MD, PhD, both of University of Calgary, Alberta, in an accompanying editorial.

“Although the traditional rationale for ivabradine is exclusively about its direct effects on the sinus node, perhaps there are also central nervous system effects that blunt sympathetic nerve outflow,” they stated.

“Let us hope that this is just the beginning of a new era of rigorous, controlled, and at least modestly long clinical trials that provide high-quality evidence to guide the management of patients with POTS,” Raj and Sheldon wrote.

Raj’s group is embarking on a trial comparing ivabradine with the beta blocker propranolol in POTS. Recently, the team reported some benefit to a waist-high compression garment in this population.

POTS remains a poorly understood, heterogenous disorder with no class I recommended therapies. Patients, predominantly young women, have heart rate quicken when moving from a supine to a standing position, which may be accompanied by a wide spectrum of symptoms such as lightheadedness or dyspnea.

For people with hyperadrenergic POTS, the subtype related to elevated norepinephrine levels, abnormal sympathetic nervous system activation is implicated. “The body is in a constant ‘flight or fight’ mode, which results in abnormal responses including elevated heart rate and decreased perfusion of organs,” according to Taub and colleagues.

They suggested stratifying POTS patients by norepinephrine levels to identify those who may benefit from ivabradine.

The present trial had a placebo-controlled crossover design. Participants were randomized to start either ivabradine (2.5-7.5 mg twice daily) or placebo for 1 month, undergo a 1-week washout period, then crossover to the other treatment for another month.

Taub’s group randomized 26 people with hyperadrenergic POTS, defined as plasma norepinephrine over 600 pg/mL and an abnormal tilt table test. Of this group, 22 completed the study (average age 33.9, 95.5% women, 86.4% white).

One person dropped out on placebo due to other health concerns; three dropped out from the ivabradine phase due to nausea and drowsiness after three days, fatigue after 21 days, and phosphenes after four days.

The authors acknowledged their small sample and short study duration. Additionally, they noted that although investigators and patients had been blinded, many patients were able to guess when they were on ivabradine.

“It is not clear why the authors studied only the hyperadrenergic population, and this unfortunately limits the evidence-based use of ivabradine. As well, the apparent effects of ivabradine on the sympathetic response to orthostatic stress may simply be a sampling error, and unquestionably deserves further study,” added Raj and Sheldon.

The editorialists also pointed out that standing heart rate in the placebo phase was only 94 beats/min, suggestive of only mild POTS. Most study participants technically did not experience POTS during the study, which raises the question of whether ivabradine was actually tested in people with active POTS, they said.

Nevertheless, the results are “particularly gratifying” given the lack of effective treatments for POTS and the long-awaited arrival of randomized data on ivabradine’s potential benefit, according to Raj and Sheldon.