Mij
Senior Member (Voting Rights)
What is the clinical question being addressed?
Does ivabradine or propranolol more effectively reduce orthostatic tachycardia and symptoms in POTS?
What is the main finding?
Both ivabradine and propranolol reduce tachycardia and symptoms in POTS, supporting their use, but variability in response suggests that individualized treatment selection is warranted.
Postural orthostatic tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterized by an exaggerated increase in heart rate (HR: >30 beats/min) within 10 minutes of standing, in the absence of orthostatic hypotension (blood pressure drop >20/10 mm Hg).1, 2, 3 POTS is associated with a variety of chronic (>3 months), debilitating cardiovascular and neurological symptoms, which improve with recumbence.3 Despite its prevalence and functional impact, no pharmacologic therapies are approved. Ivabradine and propranolol are commonly prescribed off-label, but no randomized trial has directly compared these medications.
We conducted a randomized, double-blind, placebo-controlled crossover trial comparing ivabradine and propranolol in patients with POTS. Full methodological and analytic detail is provided in our JACC: Advances article,4 published concurrently with this feature.
A total of 28 patients with POTS (age 33 ± 9 years; 100% women) completed 3 4-week treatment phases (ivabradine 5 mg twice daily; propranolol 10 mg 4 times daily; placebo) in randomized order with 7-day washout periods between phases. Each phase concluded with a 10-minute head-up tilt test (HUT) with continuous beat-to-beat hemodynamic monitoring. The primary outcome was the delta peak HR (ΔHRPeak), calculated as upright HR minus baseline, during the last 5-minutes of HUT. Secondary outcomes included absolute peak HR (HRPeak), upright delta hemodynamics including systolic blood pressure (SBP) and diastolic blood pressure, cardiac output, stroke volume, systemic vascular resistance, 24-hour Holter monitor recordings, quality-of-life measures, the Cambridge Neuropsychological Test Automated Battery to assess reaction time (psychomotor function), and medication preference.
This study was approved by the University of Calgary Ethics Board (REB19-1437) and the data reported are a part of the Crossover Study of Propranolol vs Ivabradine in POTS.
Results
All 28 participants completed hemodynamic testing for each phase. During HUT, ΔHR was reduced for ivabradine compared with placebo (24 beats/min vs 33 beats/min; P<em>Drug</em> < 0.001) and propranolol compared with placebo (25 beats/min vs 33 beats/min; P<em>Drug</em> < 0.001). There was no difference between the active medications (22 beats/min vs 23 beats/min; P<em>Drug</em> = 0.09). Ivabradine demonstrated a larger magnitude increase in ΔSBP compared with propranolol (4.9 mm Hg vs 1.9 mm Hg; P<em>Drug</em> = 0.001).
Compared with placebo, the HRPeak was lower for ivabradine (99 ± 3 beats/min vs 118 ± 3 beats/min; P < 0.001) (Figure 1A) and demonstrated a reduced ΔHRPeak (27 ± 2 beats/min vs 36 ± 2 beats/min; P = 0.001) (Figure 1B). Compared with placebo, the HRPeak was lower for propranolol (100 ± 3 beats/min vs 118 ± 3 beats/min; P < 0.001) (Figure 1C) and demonstrated a reduced ΔHRPeak (28 ± 2 beats/min vs 36 ± 2 beats/min; P = 0.005) (Figure 1D). Cardiac output at HRPeak was lower for propranolol compared with placebo (4.7 ± 0.3 L/min vs 5.2 ± 0.3 L/min; P = 0.001), while systemic vascular resistance at HRPeak was higher for propranolol compared with placebo (1,650 ± 148 dyn·s·cm−5 vs 1416 ± 119 dyn·s·cm−5; P = 0.01). The HRPeak was not different between ivabradine and propranolol (99 ± 3 beats/min vs 100 ± 3 beats/min; P = 0.56) (Figure 1E) and demonstrated a similar ΔHRPeak (27 ± 2 beats/min vs 28 ± 2 beats/min; P = 0.42) (Figure 1F). Both active treatments reduced ΔHRPeak below the diagnostic threshold for POTS (≥30 beats/min).
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Does ivabradine or propranolol more effectively reduce orthostatic tachycardia and symptoms in POTS?
What is the main finding?
Both ivabradine and propranolol reduce tachycardia and symptoms in POTS, supporting their use, but variability in response suggests that individualized treatment selection is warranted.
Postural orthostatic tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterized by an exaggerated increase in heart rate (HR: >30 beats/min) within 10 minutes of standing, in the absence of orthostatic hypotension (blood pressure drop >20/10 mm Hg).1, 2, 3 POTS is associated with a variety of chronic (>3 months), debilitating cardiovascular and neurological symptoms, which improve with recumbence.3 Despite its prevalence and functional impact, no pharmacologic therapies are approved. Ivabradine and propranolol are commonly prescribed off-label, but no randomized trial has directly compared these medications.
We conducted a randomized, double-blind, placebo-controlled crossover trial comparing ivabradine and propranolol in patients with POTS. Full methodological and analytic detail is provided in our JACC: Advances article,4 published concurrently with this feature.
Methods
Detailed trial protocol, monitoring implementation, and operationalization experience are presented in the companion paper.A total of 28 patients with POTS (age 33 ± 9 years; 100% women) completed 3 4-week treatment phases (ivabradine 5 mg twice daily; propranolol 10 mg 4 times daily; placebo) in randomized order with 7-day washout periods between phases. Each phase concluded with a 10-minute head-up tilt test (HUT) with continuous beat-to-beat hemodynamic monitoring. The primary outcome was the delta peak HR (ΔHRPeak), calculated as upright HR minus baseline, during the last 5-minutes of HUT. Secondary outcomes included absolute peak HR (HRPeak), upright delta hemodynamics including systolic blood pressure (SBP) and diastolic blood pressure, cardiac output, stroke volume, systemic vascular resistance, 24-hour Holter monitor recordings, quality-of-life measures, the Cambridge Neuropsychological Test Automated Battery to assess reaction time (psychomotor function), and medication preference.
This study was approved by the University of Calgary Ethics Board (REB19-1437) and the data reported are a part of the Crossover Study of Propranolol vs Ivabradine in POTS.
Results
All 28 participants completed hemodynamic testing for each phase. During HUT, ΔHR was reduced for ivabradine compared with placebo (24 beats/min vs 33 beats/min; P<em>Drug</em> < 0.001) and propranolol compared with placebo (25 beats/min vs 33 beats/min; P<em>Drug</em> < 0.001). There was no difference between the active medications (22 beats/min vs 23 beats/min; P<em>Drug</em> = 0.09). Ivabradine demonstrated a larger magnitude increase in ΔSBP compared with propranolol (4.9 mm Hg vs 1.9 mm Hg; P<em>Drug</em> = 0.001).
Compared with placebo, the HRPeak was lower for ivabradine (99 ± 3 beats/min vs 118 ± 3 beats/min; P < 0.001) (Figure 1A) and demonstrated a reduced ΔHRPeak (27 ± 2 beats/min vs 36 ± 2 beats/min; P = 0.001) (Figure 1B). Compared with placebo, the HRPeak was lower for propranolol (100 ± 3 beats/min vs 118 ± 3 beats/min; P < 0.001) (Figure 1C) and demonstrated a reduced ΔHRPeak (28 ± 2 beats/min vs 36 ± 2 beats/min; P = 0.005) (Figure 1D). Cardiac output at HRPeak was lower for propranolol compared with placebo (4.7 ± 0.3 L/min vs 5.2 ± 0.3 L/min; P = 0.001), while systemic vascular resistance at HRPeak was higher for propranolol compared with placebo (1,650 ± 148 dyn·s·cm−5 vs 1416 ± 119 dyn·s·cm−5; P = 0.01). The HRPeak was not different between ivabradine and propranolol (99 ± 3 beats/min vs 100 ± 3 beats/min; P = 0.56) (Figure 1E) and demonstrated a similar ΔHRPeak (27 ± 2 beats/min vs 28 ± 2 beats/min; P = 0.42) (Figure 1F). Both active treatments reduced ΔHRPeak below the diagnostic threshold for POTS (≥30 beats/min).
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