1.0 BACKGROUND Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic
intolerance characterized by symptoms of palpitations, lightheadedness, chest discomfort,
shortness of breath, blurred vision, and mental clouding. These symptoms occur during
standing and are associated with a marked increase in heart rate (HR) in the absence of
hypotension, which typically resolve when sitting or lying down. Most importantly, POTS is
associated with a very poor quality of life and significant functional disability. POTS
patients commonly experience mental clouding ("brain fog") even while lying down or seated,
which poses significant limitations to daily activities .
Unfortunately, there is a relative paucity in the literature assessing therapies for POTS
patients. Given that excessive tachycardia on standing is a fundamental component of this
syndrome, a handful of studies have evaluated medications that reduce HR. In a randomized
crossover study of 54 patients with POTS, low-dose propranolol (10-20 mg PO) was found to
acutely reduce standing HR compared to placebo. Further, there was greater improvement in
symptom burden (quantified using the Vanderbilt Orthostatic Symptom Score [VOSS]) from
baseline to 2 hours in patients treated with propranolol compared to placebo.
Ivabradine is newer drug that is a selective If channel blocker that reduces HR without
affecting other cardiovascular functions. In non-randomized reports, it has been shown to
improve symptoms in patients with POTS. In a case series of 22 patients, approximately 60% of
patients with POTS treated with ivabradine had symptom improvement
2.0 RATIONALE / STUDY PURPOSE Patients with POTS suffer great disability and currently used
pharmacologic therapies require more rigorous study. Currently, there are no studies
comparing the relative efficacy of propranolol and ivabradine in patients with POTS.
We propose to compare the efficacy of propranolol and ivabradine on HR response to standing,
and symptom burden in patients with POTS. This would be the first study to compare the
relative efficacy of ivabradine to propranolol in POTS. The results of this exploratory study
may help inform design of a larger multicenter clinical trial investigating the use of
ivabradine or propranolol in POTS over time. We will test the null hypothesis that the heart
rate lowering response to ivabradine is not different than the heart lowering response of
propranolol.
In addition, we propose to assess sleep complaints and sleep quality using questionnaire and
actigraphy based assessments.
3.0 Study Design This will be a multi-center double-blind placebo-controlled randomized
crossover trial conducted in patients with POTS to compare effects of (1) oral ivabradine 5
mg bid plus placebo BID (to fill out a QID schedule); (2) oral propranolol 10 mg qid; and (3)
oral placebo qid in POTS patients. After a baseline screening assessment following a washout
period of 7 days, participants will be randomized to start with a 4-week course of either
ivabradine, propranolol or placebo. The other two treatments will be given in separate 4-week
courses with a 7-day washout period between phases, with each participant acting as his or
her own control. At the end of each 4-week phase, participants will complete the
symptom-rating and HRQOL questionnaires, and also undergo tilt table testing to assess the
change in HR at 10 min with head up tilt.
Participants will undergo POTS testing at baseline and at the end of each 4-week treatment
course in the Libin Cardiovascular Institute TRW Human Physiology Research space. This will
involve a total of 4 separate study visits.
•• Studies will start between 8-9am, with the patient in a fasting state (to avoid acute
hemodynamic effects from eating).
Prior to hemodynamic data collection, a brief medical history will be conducted to
ensure that the medications have not changed, and that there are not new medical issues
that would make the study unsafe or imprudent.
Participants will be instrumented for continuous beat-to-beat BP and
electrocardiographic monitoring. BP will be monitored continuously using a finger volume
clamp method (Nexfin, BMEYE Inc.) and calibrated with intermittent brachial cuff
measurements using a standard automatic BP monitor (IVY Model 450C, IVY Medical,
Branford, CT, USA) or by using Finapres NOVA, Finapres Medical Systems .
Baseline seated continuous data (EKG signals and continuous BP will be collected for ~10
min).
Neuropsychological testing of the cognitive domains of memory, attention and executive
function will be assessed using the Cambridge Neuropsychological Test Automated Battery
(CANTAB) while seated.
The patient will be asked to stand and repeat portions of the CANTAB tests
Baseline lying down continuous data (EKG signals and continuous BP will be collected for
~10 min).
The patient will then be strapped onto the tilt table and then tilted to 80° head-up for
10 minutes with continuous hemodynamic data collection. Oxygen saturation will be
assessed from a finger probe. End-tidal CO2 will be measured using nasal prongs.
Participants will be asked to comment on any side effects or unrated symptoms.
VOSS ratings will be collected at the end of tilt.
Participants and the research staff will be asked to "guess" at which intervention was
given on that study day (not applicable to baseline visit).
After the study is finished, we will remove the recording patches, and electrodes. This
testing day will last about 3 hours.
Upon conclusion of the tilt testing, we will connect patients to a 24-hour Holter monitor for
continuous ECG and HR monitoring. Participants will return the monitoring device the
following day.
This testing protocol will be repeated at baseline, and at the end of phase 1, 2, and 3 with
different study drugs.