Crossover Study of Propranolol vs Ivabradine in POTS
Crossover Study of Propranolol vs Ivabradine in POTS
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. Ivabradine is newer
 drug that is a selective If channel blocker that reduces HR without affecting other
 cardiovascular functions.

 2.0 RATIONALE / STUDY PURPOSE The investigators propose to compare the efficacy of
 propranolol and ivabradine on HR response to standing, and symptom burden in patients with
 POTS.

 3.0 Study Design This will be a single-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 20 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. This will involve a total of 4 separate study visits.
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 20 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.
Inclusion Criteria:

 -  Diagnosis of Postural Tachycardia Syndrome

 -  Age between 18-60 years

 -  Men and women are eligible

 -  Able and willing to provide informed consent

 Exclusion Criteria:

 -  Seated resting heart rate < 70 bpm in the absence of rate-lowering medications

 -  Supine blood pressure < 90/60 mmHg

 -  Overt cause for postural tachycardia, i.e., acute dehydration, prolonged bed rest

 -  Presence of underlying structural heart disease including:

 -  Valvular disease (i.e. moderate or greater valvular stenosis or regurgitation)

 -  History of heart failure

 -  Greater than mild left ventricular systolic impairment

 -  Hypertrophic cardiomyopathy

 -  Known coronary artery disease or prior myocardial infarction

 -  History of tachyarrhythmias including:

 -  Supraventricular tachycardia, atrial tachycardia, atrial fibrillation / flutter

 -  Ventricular tachyarrhythmias

 -  Pre-existing long QT interval (e.g. known congenital long QT syndrome, or QT interval
 >500 ms)

 -  History of sick sinus syndrome or high degree AV block

 -  Presence of a pacemaker, implantable cardioverter defibrillator or cardiac
 resynchronization therapy device

 -  Diabetes mellitus or history of hypoglycemic episodes

 -  History of bronchospasm or uncontrolled asthma

 -  Pregnant (by history or serum test) or breast-feeding

 -  Inability to safely withdraw from existing beta-blockers or ivabradine prior to the
 study day

 -  Concomitant use of class I and III antiarrhythmic agents, or non-dihydropyridine
 calcium channel blockers

 -  Concomitant use of strong cytochrome P450 3A4 (CYP 3A4) inhibitors

 -  Severe hepatic impairment

 -  Any contraindication to propranolol or ivabradine not specifically listed above as per
 the product monographs.

 -  Unable to give informed consent