Reviews
Preventing and treating orthostatic hypotension: As easy as A, B, C
Easy-to-remember management recommendations, using a combination of effective drug and nondrug treatments.
DRUG THERAPY
No medications are approved by the US Food and Drug Administration (FDA) or Health Canada specifically for treating POTS, making all pharmacologic recommendations off-label. Although the drugs discussed below have been evaluated for POTS in controlled laboratory settings, they have yet to be tested in robust clinical trials.
Blood volume expansion
Several drugs expand blood volume, which may reduce orthostatic tachycardia.
Fludrocortisone is a synthetic aldosterone analogue that enhances sodium and water retention. Although one observational study found that it normalizes hemodynamic changes in response to orthostatic stress, no high-level evidence exists for its effectiveness for POTS.55 It is generally well tolerated, although possible adverse effects include hyperkalemia, hypertension, fatigue, nausea, headache, and edema.5,56
Desmopressin is a synthetic version of a natural antidiuretic hormone that increases kidney-mediated free-water reabsorption without sodium retention. It significantly reduces upright heart rate in patients with POTS and improves symptom burden. Although potential adverse effects include edema and headache, hyponatremia is the primary concern with daily use, especially with the increased water intake advised for POTS.57 Patients should be advised to use desmopressin no more than once a week for the acute improvement of symptoms. Intermittent monitoring of serum sodium levels is recommended for safety.
Erythropoietin replacement has been suggested for treating POTS to address the significant deficit in red blood cell volume. Although erythropoietin therapy has a direct vasoconstrictive effect and largely improves red blood cell volume in patients with POTS, it does not expand plasma volume, so orthostatic tachycardia is not itself reduced.22 Nevertheless, it may significantly improve POTS symptoms refractory to more common methods of treatment, and it should be reserved for such cases. In addition to the lack of effect on orthostatic tachycardia, drawbacks to using erythropoietin include its high cost, the need for subcutaneous administration, and the risk of life-threatening complications such as myocardial infarction and stroke.58,59
Heart rate-lowering agents
Propranolol, a nonselective beta-adrenergic antagonist, can significantly reduce standing heart rate and improve symptoms at low dosages (10–20 mg). Higher dosages can further restrain orthostatic tachycardia but are not as well tolerated, mainly due to hypotension and worsening of existing symptoms such as fatigue.60 Regular-acting propranolol works for about 4 to 5 hours per dose, so full-day coverage often requires dosing 4 times per day.
Ivabradine is a selective blocker of the “funny” (If) channel that reduces the sinus node firing rate without affecting blood pressure, so it slows heart rate without causing supine hypertension or orthostatic hypotension.
A retrospective case series found that 60% of patients with POTS treated with ivabradine reported symptomatic improvement, and all patients experienced reduced tachycardia with continued use.61 Ivabradine has not been compared with placebo or propranolol in a randomized controlled trial, and it has not been well studied in pregnancy and so should be avoided because of potential teratogenic effects.
When prescribing ivabradine for women of childbearing age, a negative pregnancy test may be documented prior to initiation of therapy, and the use of highly effective methods of contraception is recommended. Ivabradine should be avoided in women contemplating pregnancy. Insurance coverage can limit access to ivabradine in the United States.
Central nervous system sympatholytics
Patients with prominent hyperadrenergic features may benefit from central sympatholytic agents. However, these drugs may not be well tolerated in patients with neuropathic POTS because of the effects of reduced systemic vascular resistance5 and the possible exacerbation of drowsiness, fatigue, and mental clouding.4 Patients can be extremely sensitive to these medications, so they should initially be prescribed at the lowest dose, then gradually increased as tolerated.
Clonidine, an alpha-2-adrenergic agonist, decreases central sympathetic tone. In hyperadrenergic patients, clonidine can stabilize heart rate and blood pressure, thereby reducing orthostatic symptoms.62
Methyldopa has effects similar to those of clonidine but is easier to titrate owing to its longer half-life.63 Methyldopa is typically started at 125 mg at bedtime and increased to 125 mg twice daily, if tolerated.