Management of coexistent neurogenic orthostatic hypotension and supine hypertension

One of the most challenging clinical dilemmas is treating a patient with neurogenic orthostatic hypotension (nOH) who also has supine hypertension (SH), a frequent occurrence in patients with autonomic failure. nOH and SH represent opposing hemodynamics, and managing the coexistent conditions can be difficult because therapy for one may cause or exacerbate the other. Unfortunately, because an optimal simultaneous management strategy has not yet been identified through systematic study, health care providers must base treatment decisions on their clinical experience and judgment, supplemented by information from published expert opinions.1-3 Neurogenic orthostatic hypotension is characterized as a systolic blood pressure (BP) drop ≥ 20 mm Hg or diastolic BP drop ≥ 10 mm Hg within 3 minutes of standing as a consequence of dysfunctional BP regulatory mechanisms mediated through autonomic nervous system responses.2, 4 nOH is a manifestation of inadequate vasoconstriction due to norepinephrine deficiency upon orthostatic challenge and frequently occurs in patients with neurologic diseases associated with autonomic failure.2, 4 nOH has a distinct etiology from other non-neurogenic causes of OH, such as medications use (eg, diuretics, vasodilators, and antidepressants) or clinical conditions (eg, hypovolemia, deconditioning, and impaired cardiac output).2, 4 The dysfunctional autonomic BP control mechanisms and multifaceted loss of baroreflex restraint responsible for nOH also underlie the occurrence of SH (defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg while in the supine position).1, 2 Although SH occurs as a pathophysiologic consequence of autonomic dysfunction, antihypotensive agents used in the treatment of nOH can further exacerbate the condition.1 When treating patients with nOH and SH, clinicians must weigh the relative risk and benefits of any treatment approach. Common symptoms of nOH include dizziness/lightheadedness, syncope, presyncope, cognitive difficulties, neck pain (ie, “coat hanger” pain), fatigue, and weakness,2, 4 which can lead to an increased risk of falls and fall-related injuries.2, 5-8 Although decreasing fall risk is an important safety consideration, clinicians also should be aware of the growing body of evidence demonstrating the substantial physical and psychosocial patient burden associated with nOH, including less ability to perform daily activities and negative effects on wellbeing (eg, measures of anxiety, quality of life, and perception of independence).5-7 Additionally, the burden of nOH may extend beyond the individual patient based on data showing that the condition is associated with greater health care resource use.6, 8, 9 Because of the symptomatic burden and fall risk associated with nOH, management of this condition usually takes priority to reduce the patient's symptoms and improve daily function2; nevertheless, the risks of uncontrolled SH must also be considered. Although there are limited data specific to the hypertensive risk in patients with nOH, studies of patients with autonomic failure suggest that SH is associated with potentially poor outcomes including cardiovascular damage (left ventricular hypertrophy), decreased renal function (lower estimated glomerular filtration rate and higher creatinine), and an increased risk of cardiovascular morbidity and mortality.10-12 Further, SH increases nocturnal pressure natriuresis, causing nocturia and volume loss overnight, which can lead to worsened nOH symptoms the following morning.2, 4 Taken together, these data indicate that both nOH and SH should be effectively managed through an integrated therapeutic approach, such as the one used in the following case. A 60-year-old woman presented with symptomatic orthostasis, frequent syncopal spells (≥5 times per week), and a syncope-related femoral fracture. Orthostatic BP measurements revealed a supine BP of 150/70 mm Hg (ie, SH) with nOH occurring upon standing (standing BP 70 to 80/50 mm Hg; ie, 80 mm Hg of orthostatic hypotension [OH]). The patient did not use diuretics, was euvolemic, with no evidence of systemic neurologic disease or diabetes. The patient received a pacemaker; however, her hemodynamic issues remained unresolved. She was hospitalized, and midodrine (titrated to 20 mg 3 times daily [TID]; initial dose, 2.5 mg) and losartan at bedtime (titrated to 100 mg; initial dose, 50 mg) were used to manage the nOH and SH, respectively. This treatment regimen resulted in a 50-mm Hg decrease in orthostatic BP with resolution of syncope; however, the patient experienced occasional lightheadedness. After hospital discharge, her SH became more severe (systolic BP ≤ 200 mm Hg), so the midodrine dose was decreased to 10 mg TID, and clonidine at bedtime (0.1-0.2 mg) was prescribed. However, her syncope recurred on this treatment regimen, and she experienced a small hemorrhagic stroke, possibly due to midodrine-induced hypertension. The patient was rehospitalized, midodrine was discontinued, and instead, droxidopa (titrated to 300 mg TID) was prescribed for nOH management. The use of droxidopa resulted in a 40-mm Hg decrease in orthostatic BP and was well tolerated. The patient has been successfully treated with droxidopa for 3 years with no reported incidences of syncope or falls. In this patient, both midodrine and droxidopa, the 2 drugs currently approved by the US Food and Drug Administration for the treatment of OH/nOH, were tried. Ultimately, droxidopa, a norepinephrine prodrug approved for the treatment of the nOH symptoms of dizziness/lightheadedness in patients with autonomic failure conditions,13 improved the patient's symptoms and alleviated her severe SH, with reduction of SH spikes. With midodrine, an α1 adrenergic agonist prodrug approved for symptomatic OH,14 the patient still experienced occasional lightheadedness, and her SH worsened. These observations underscore much of the clinical data for each drug. Droxidopa has been shown to improve the common symptoms of nOH (eg, dizziness/lightheadedness) in short-term randomized clinical trials,15-17 but effectiveness beyond 2 weeks has not been established in controlled studies.13 In a longer-term real-world study (up to 6 months), patients reported improvements in measures of nOH symptoms, physical function, and quality of life after 1, 3, and 6 months of open-label droxidopa treatment.18 Much of the clinical evidence supporting midodrine is based on increased standing BP, which is considered a surrogate marker for clinical benefit for improvement of orthostatic symptoms.14, 19, 20 Because both midodrine and droxidopa elevate BP by causing vasoconstriction, each carries a boxed warning in their labels for the risk of causing or exacerbating SH.13, 14 However, a 2018 meta-analysis suggests a potential difference in the SH risks between droxidopa and midodrine.21 This study identified a significantly increased risk of SH with midodrine (risk ratio [RR], 5.1 vs placebo, 2 studies) but no increased risk with droxidopa (RR, 1.4 vs placebo, 4 studies).21 Although these data provide an initial quantification of the SH risks associated with these drugs, interpretation is limited by the small numbers (ie, studies, patients, and events) and relatively short follow-up periods studied. It should be noted that this meta-analysis of SH risk examined doses of droxidopa (mean dose range, 390-436 mg TID), and midodrine (2.5-10 mg TID) consistent with suggested label dosing (100-600 mg TID and 10 mg TID, respectively).13, 14, 21 In the case described, the patient was initially titrated to a relatively high dose of midodrine (20 mg TID). This dose is not generally recommended because of a high rate of severe, persistent SH (45%),14 and its use likely contributed to the patient's hemorrhagic stroke. However, severe SH (systolic BP, 210 mm Hg), which was possibly associated with a cerebrovascular event (caudate hemorrhage), has been reported with a 10-mg dose of midodrine in a patient with nOH.22 To minimize SH and its associated risks in patients with nOH, the final daily dose of any vasopressor agent (eg, droxidopa and midodrine) should be taken at least 3-4 hours before bedtime.13, 14 Patients should also be advised to avoid a completely supine resting position at any time and sleep in a bed tilted in a head-up position (ie, head raised 6-9 inches).1-3, 13, 14 Although these simple tactics are good clinical practice points in the management of all patients with nOH and may be sufficient to manage mild SH, severe, persistent SH (systolic BP > 180 mm Hg or diastolic BP > 110 mm Hg) may require pharmacologic intervention with a short-acting antihypertensive agent at night.1, 2 Appropriate choice of antihypertensive agent is critical to avoid worsening nOH symptoms the following morning.2, 3 In the scenario described, losartan and clonidine were used to improve nocturnal SH. These 2 agents have been shown to decrease overnight BP and pressure natriuresis in patients with primary autonomic failure and SH, with no effects on orthostatic tolerance the next morning.23, 24 In addition to these, other antihypertensives recommended for the treatment of SH in patients with nOH include a nitroglycerin patch, nifedipine, or hydralazine.2, 3 However, data supporting the use of any of these antihypertensive agents for management of SH in patients with nOH are somewhat limited, and individual patients may have varied responses based on many factors, including underlying disease. Further research is required in these areas. Additional areas of study include greater understanding of the morbidity and mortality risks associated with nOH and SH (individually and coexistent) and determination of benefit of effective management of one condition on the other (ie, effect of control of nOH on SH and vice versa). Until then, clinicians will continue to need to rely on clinical judgment and advice to treat co-occurring nOH and SH. The treatment regimen such as the one detailed here may be beneficial in the successful management of these conditions. Medical writing assistance was provided by the CHC Group LLC (North Wales, PA), an ICON plc company, which was supported by Lundbeck. Dr Cannom is a speaker for Medtronic and has served as a consultant or advisory board member for Medtronic, Boston Scientific, and Lundbeck.