Curr Cardiol Rep (2014) 16:542 DOI 10.1007/s11886-014-0542-z

HYPERTENSION (W WHITE, SECTION EDITOR)

New Developments in the Management of Neurogenic Orthostatic Hypotension Italo Biaggioni

Published online: 11 October 2014 # Springer Science+Business Media New York 2014

Abstract Orthostatic hypotension (OH) is defined as a sustained reduction of ≥20 mmHg systolic blood pressure or ≥10 mmHg diastolic blood pressure upon standing for ≤3 min. Orthostatic hypotension is commonly associated with hypertension, and its prevalence is highest in those with uncontrolled hypertension compared to those with controlled hypertension or normotensive community elderly subjects. Orthostatic hypotension can cause significant disability, with patients experiencing dizziness, lightheadedness or syncope, and other problems that potentially have a profound negative impact on activities of daily living that require standing or walking. Furthermore, OH increases the risk of falls and, importantly, is an independent risk factor of mortality. Despite its importance, there is a paucity of treatment options for this condition. Most of the advances in treatment options have relied on small studies of repurposed drugs done in patients with severe OH due to rare neurodegenerative conditions. Midodrine, an oral prodrug converted to the selective α1adrenoceptor agonist desglymidodrine, was approved by the FDA for the treatment of OH in 1996. For almost two decades, no other pharmacotherapy was developed specifically for the treatment of OH until 2014, when droxidopa was approved by the FDA for the treatment of neurogenic OH associated with primary autonomic neuropathies including Parkinson disease, multiple system atrophy, and pure autonomic failure. These are neurodegenerative diseases ultimately characterized by failure of the autonomic nervous system to generate norepinephrine responses appropriate to postural challenge. Droxidopa is a synthetic amino acid that is converted to This article is part of the Topical Collection on Hypertension I. Biaggioni (*) Division of Clinical Pharmacology, Department of Medicine, and the Autonomic Dysfunction Center, 560 RRB, Vanderbilt University, Nashville, TN 37232, USA e-mail: [email protected]

norepinephrine by dopa-decarboxylase, the same enzyme that converts levodopa into dopamine in the treatment of Parkinson disease. We will review this and other advances in the treatment of OH in an attempt to provide a practical guide to its management. Keywords Orthostatic hypotension . Hypertension . Frail elderly . Autonomic nervous system . Droxidopa

Introduction Orthostatic hypotension (OH) is an important and common condition, particularly in the elderly [1, 2]. Treatment can be challenging but can be guided by the underlying pathophysiology [3–7]. The reader is referred to more comprehensive reviewers on this topic [3–7]. The recent approval by the FDA of droxidopa for the treatment of neurogenic OH is a welcomed development in an area where most of the advances made have been based on acute proof-of-concept studies of existing medications (repurposing) and subsequent off-label use. Orthostatic hypotension (OH) is defined as a sustained reduction of systolic blood pressure (BP) of at least 20 mmHg or diastolic BP of 10 mmHg within 3 min of standing or headup tilt to at least 60° [8]. The clinical picture of OH is dominated by orthostatic symptoms which can be disabling and affect the patient’s quality of life. In addition, OH is a risk factor for syncope and falls [9, 10] and can be present in 24 to 31 % of patients evaluated in the emergency department for syncope [11, 12]. The estimate of OH-related hospitalization is 36 per 100,000 US adults, and can be as high as 233 per 100,000 in those age 75 or older. More importantly, OH is associated with incident coronary artery disease, stroke, and heart failure [13, 14], and is an independent predictor of mortality [15, 16•].

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Orthostatic Hypotension and Hypertension in the Frail Elderly Orthostatic hypotension is common in the elderly; the incidence of OH increases exponentially with age [1, 18]. It is also more common in the frail elderly; the prevalence of OH in community dwellers older than 65 years is 16.2 % [17], but it increases to 50 % or more in institutionalized patients such as those living in nursing homes. The number of prescribed medications and the presence of multiple comorbidities are predictors of OH [19, 20]. Thus, OH is most often seen in the frail elderly with numerous pathologies and polypharmacy, without an obvious single cause. The elderly are particularly prone to develop OH because aging is associated with impairment of various compensatory mechanisms to orthostasis [21–24]. Hypertension is one of the comorbidities most often associated with OH. This is not surprising given that both conditions are highly prevalent in the elderly, and agerelated autonomic impairment contributes to both. The presence of OH complicates the management of the hypertensive elderly, but antihypertensive medications should not be stopped in patients with OH. Even though the antihypertensive medications are often withheld in an attempt to ease OH, existing data indicates that such an approach produces the opposite effect; the risk of falls is nearly 2.5 times higher in elderly with uncontrolled hypertension and OH [25]. Most likely, this is caused by pressure diuresis and worsening of OH. Unfortunately, there are no studies to guide treatment in these patients, but angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may improve cerebral blood flow in elderly patients [25, 26] and may be a reasonable initial therapy for hypertension in the patient with OH. Patients with neurogenic OH may have severe hypertension in the supine position. During the day, supine hypertension is best treated simply by avoiding the supine position. At night, it can be managed by raising the head of the bed by 6 to 9 in. (to about 30°) and by the use of short-acting antihypertensive drugs given at bedtime [7].

Goals of Treatment The main goal is to reduce symptoms and improve the patients’ functional status and quality of life, rather than achieving an arbitrary upright systolic BP level. Accordingly, the FDA considers that improvement of symptoms should be the main outcome in assessing efficacy of drugs being developed for this condition, instead of an increase in upright BP. We assume that reducing orthostatic hypotension will result in prevention of syncope and falls, but this has not been shown

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for any of the therapies currently available. Less certain is if treatment will prevent mortality associated with OH. It could be argued that pharmacological treatment (e.g., with fludrocortisone or pressor agents) may even have a negative impact on cardiovascular outcomes. Current treatment recommendations are based mostly on studies in small numbers of patients with primary forms of autonomic failure and severe OH, with limited evidence of long-term efficacy or randomized controlled clinical trials [27]. There are no studies that will guide treatment in the more common situation of elderly patients with multiple comorbidities that develop orthostatic hypotension.

Pathophysiology as a Guide to Treatment In healthy individuals, changing position from supine to upright posture results in about 700 ml of venous pooling in the lower extremities and splanchnic circulation as a result of the gravitational pull. This decreases venous return to the heart, reduces ventricular filling, and transiently decreases cardiac output and blood pressure. This results in a baroreflexmediated compensatory sympathetic activation and decreased parasympathetic activity that increases venous return, heart rate, and vascular resistance with the goal of restoring cardiac output and blood pressure. Impairment in one or more of these compensatory mechanisms eventually results in OH (Fig. 1). Dehydration, volume depletion, and medications are all common causes of OH. Orthostatic hypotension, however, rarely occurs in young individuals with preserved autonomic function. If it does, the underlying cause is usually readily apparent. More often, it occurs in association with impaired or blunted autonomic reflexes, and this is likely the reason OH is more common in the elderly. More severe failure of reflex neural pathways (autonomic neuropathy) will result in neurogenic OH, which is characterized by profound OH without an “adequate” compensatory heart rate increase (usually 20 mmHg). The common disorders that lead to autonomic neuropathies include diabetes and diseases causing peripheral neuropathies and small fiber neuropathies. Less common are primary neurodegenerative diseases of the autonomic nervous system, including Parkinson disease, pure autonomic failure, and multiple system atrophy. Most of the research in this area is done in patients with these primary forms of autonomic neuropathy and the available data are generated in these patients. This is important to consider when treating the vast majority of patients with OH—which are typically frail elderly patients with multiple morbidities and polypharmacy (see below). Nonetheless, understanding the underlying pathophysiology will help guide treatment in all cases.

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Fig. 1 Pathophysiological changes occurring during upright posture (left panel) and corresponding approaches to treatment of OH (right panel)

General Countermeasures The first step in the management of OH involves the removal of any potential factor that could precipitate or contribute to OH. Medications are among the common offenders. Amitriptyline, often used to treat pain in sensory neuropathies (which is often seen in patients with autonomic neuropathies), is a common culprit. In patients with hypertension and OH, we should avoid certain medications, such as diuretics and alpha-blockers, but not abandon antihypertensive treatment altogether (see above). Physicians also need to be aware of “hidden” anti-adrenergic agents. Tamsulosin, commonly used to treat benign prostatic hyperplasia, is an alpha-blocker with preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in blood vessels. This selectivity, however, is not absolute, and tamsulosin increases the risk of orthostatic hypotension in susceptible individuals [28•]. Similarly, the “central muscle relaxant” tizanidine is in the same class of α2 agonists as clonidine and can also cause orthostatic hypotension [29]. Patients should be encouraged to increase salt and water consumption up to 6–10 g of sodium chloride daily and 1.5– 2 L of water a day. Ideally, patients can add 1–2 teaspoon of salt to a healthy diet. If needed, patients can use sodium chloride tablets (1 g with each meal). These are general recommendations that should be individualized, e.g., by considering that congestive heart failure is also associated with OH [30, 31]. Physical activity is recommended to avoid deconditioning and improve functional status.

These include standing slowly and, in stages, avoid standing motionless, and tensing the leg muscles [32]. Compression stockings can be used also to decrease venous pooling on standing, but because most of the pooling occurs in the abdomen [33], waist-high stockings that produce at least 15–20 mmHg pressure can be useful, but they are difficult to put on, limiting compliance. Many patients and physicians rely on knee- or thigh-high stockings, but experimental data indicate that leg compression does not improve orthostatic tolerance. On the other hand, selective abdominal compression is effective [34]. This provides a rationale to use abdominal binders, worn as tight as possible, as an alternative to waist-high compression stockings. Fludrocortisone is a synthetic mineralocorticoid aldosterone analog that is often used to treat OH [35] under the concept that it expands intravascular volume by increasing renal sodium re-absorption. This increase in plasma volume, however, is only transient and plasma volume returns to baseline values in about 2 weeks [36] likely due to mineralocorticoid escape. The long-term benefit of fludrocortisone may be related to potentiation of the pressor effect of norepinephrine and angiotensin II. Fludrocortisone should not be given in patients with congestive heart failure. Recombinant erythropoietin is arguably a more effective way to increase intravascular volume and is effective in the treatment of OH [37]. However, potential adverse events and expense limit the use of erythrocyte-stimulating agents.

Harness Residual Sympathetic Tone Improve Venous Return Patients should use physical countermeasures that reduce venous pooling, thereby improving venous return and cardiac output.

Even in severely affected patients, it is possible to potentiate residual sympathetic tone to improve upright BP. Atomoxetine can increase norepinephrine at the level of the noradrenergic synapse by inhibiting the reuptake of this

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catecholamine. Indeed, atomoxetine can improve orthostatic tolerance in some, but not all, autonomic failure patients even when used in pediatric doses (18 mg) [38]. Pyridostigmine is a cholinesterase inhibitor that potentiates the actions of acetylcholine and facilitates cholinergic neurotransmission in autonomic ganglia. This may lead to an increase in BP that is preferentially seen on standing, when residual sympathetic tone is increased. Indeed, pyridostigmine 60 mg increases upright BP and reduces symptoms in patients with OH and has the added advantage of not affecting supine BP [39]. However, it may not be as potent in patients with severe neurogenic OH [40•], and dose escalation is limited by side effects (abdominal cramping and other GI side effects, and urinary urgency).

Short-Acting Pressor Agents The goal of treatment is to improve orthostatic tolerance, and therefore, it would make sense to use short-acting pressor agents that would act only when patients are upright. Most of these agents have a peak effect at about 1 h and, therefore, should be given 30–45 min before upright activity, and may improve symptoms for 2–3 h or more, depending on the pharmacodynamics of a given agent. Conversely, they should never be used with patients who remain supine because they will worsen supine hypertension, induce pressure diuresis, and, through this mechanism, paradoxically worsen OH. Arguably the best example of this approach is the pressor effect of a bolus ingestion of 16 oz of tap water. This can produce dramatic increases in BP in autonomic failure patients, highlighting their lack of baroreflex buffering that unmasks the effects of seemingly trivial interventions. This can be used as a rescue measure because it acts quickly; the increase in BP is apparent in the first 5–10 min and peaks around 30 min, but it is short-lived. The increase in BP is not due to a volume effect, because the same amount of saline infused intravenously has no effect on BP. Animal studies suggest that the pressor effect of oral water is mediated by a decreased osmolality in the portal circulation that triggers a sympathetic reflex [41•]. This finding exemplifies the advantage of studying these unique patients, which allow us to unmask physiological reflexes that had previously eluded us. Until recently, the only medication approved for the treatment of OH was the alpha-1 adrenergic agonist midodrine. Treatment should begin with a 2.5- to 5-mg dose, which can then be increased up to 10 mg thrice daily. Midodrine was approved in 1996 for the treatment of symptomatic orthostatic hypotension based on studies showing an improvement in 1min standing systolic pressure. The FDA granted accelerated approval using the increase in BP as a surrogate end point, with the understanding that post-marketing studies would be performed to determine if midodrine provided a clinical

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benefit, i.e., reduce orthostatic symptoms and increase activities of daily living [42]. These studies were only started in 2012 [43], recruitment has been completed (NCT01515865, NCT01518946) but results have not been reported. Given this experience, the FDA now requires that drugs developed for the treatment of OH used symptomatic improvement as the primary outcome in clinical trials. Droxidopa was developed under these new FDA guidelines. Droxidopa (L-threo-3,4-dihydroxyphenylserine, Lthreo-DOPS, or L-DOPS) [44] is structurally similar to norepinephrine but has an additional carboxyl group (Fig. 2). It is absorbed orally and is converted to norepinephrine through the enzyme dopa-decarboxylase (L-aromatic amino acid decarboxylase (LAAD)) that is ubiquitous in tissues. This is the same enzyme that converts levodopa to dopamine for the treatment of Parkinson disease. There are four stereoisomers of DOPS, but only the L-threo-enantiomer is a substrate for LAAD and, therefore, the only one that is effective. Droxidopa was originally developed by Sumitomo Pharmaceuticals and has been approved in Japan since 1989 for the treatment of neurogenic orthostatic hypotension and the freezing phenomenon seen in patients with Parkinson disease. The efficacy of droxidopa in restoring norepinephrine is exemplified in patients with dopamine-beta-hydroxylase (DβH) deficiency. These extremely rare patients have a genetic deficiency in dopamine-β-hydroxylase, the enzyme that converts dopamine to norepinephrine (Fig. 2) and therefore accumulate dopamine and are unable to produce norepinephrine [45, 46]. Droxidopa bypasses this enzymatic defect and restores norepinephrine in these patients [47, 48]. It not only increases plasma norepinephrine but also restores it in noradrenergic nerve terminals [49]. Droxidopa reaches a peak plasma level at about 3 h after oral administration in patients with autonomic failure and has a half-life of 2–3 h [50, 51]. Plasma norepinephrine levels peak at about 3–5 h after droxidopa administration and are only one thousandth of the peak droxidopa plasma levels [50, 51]. The decay in plasma norepinephrine is slower than the half-life of droxidopa, which is notable given that the half-life of norepinephrine is 1–2 min, suggesting continued conversion of droxidopa to generate norepinephrine [44]. Therefore, the increase in BP after a single dose peaks at about 3–4 h and persists for about 6 h. Several small studies have concluded that droxidopa is effective in the treatment of OH [52, 53]. Most studies have focused on patients with severe OH (average orthostatic decreases in systolic blood pressure of 50–60 mmHg) due to primary forms of autonomic failure (pure autonomic failure, Parkinson disease, and multiple system atrophy). Droxidopa was found to increase upright BP and reduce orthostatic symptoms either after a single dose (range 200–2,000 mg) in doubleblind randomized studies [51, 54] or after a 6-week open-label study at doses ranging from 100 to 300 twice daily [55].

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Fig. 2 Catecholamine synthesis and enzymatic conversion of droxidopa into norepinephrine by dopa-decarboxylase (L-aromatic amino acid decarboxylase, LAAD), the same enzyme that converts levodopa (chemically identical to dopa) into dopamine. PNMT phenylethanolamine Nmethyltransferase

High doses of carbidopa, the LAAD inhibitor, used to prevent the conversion of levodopa to dopamine in the periphery when treating Parkinson disease also prevents the peripheral conversion of droxidopa to norepinephrine [51]. At doses used clinically, it is unclear if carbidopa would preclude the pressor effects of droxidopa [53], but patients may require a higher dose of droxidopa. Post hoc analysis of Parkinson patients participating in current clinical droxidopa trials will be revealing in this regard. More recently, the results of a multicenter, randomized, placebo-controlled study involving 162 patients with neurogenic OH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or non-diabetic autonomic neuropathy have been published [56••]. More common causes of OH (e.g., diabetic neuropathy) were not included, in keeping with the development of the drug for orphan product designation. There was an initial open-label dose titration phase (from 100 to 600 mg thrice daily), highlighting the need to individualize the dose because of the wide range of sensitivity these patients can present. Only responders (62 % of patients enrolled) were then randomized to placebo or droxidopa (enrichment design) for a 7-day treatment period. The mean dose in the droxidopa

group was 430±163 mg thrice daily. Droxidopa significantly improved orthostatic symptoms (Fig. 3a), as assessed by the change in overall composite score of a validated symptom questionnaire (orthostatic hypotension questionnaire, OHQ) [57], the primary end point. It also significantly improved upright blood pressure compared to placebo (Fig. 3b), but differences between groups were modest. This was mostly due to the fact that patients in the placebo group also improved their standing BP during the study (Fig. 3b). We speculate that this finding represents a better adherence to generally recommended countermeasures (increase fluid and salt intake, avoidance of the supine position, etc.) by patients participating in a closely controlled clinical trial. The magnitude of this effect was unforeseen and highlights the difficulties in performing clinical trials in this patient population. Patients in this study had a drop in standing systolic blood pressure in the 30- to 40-mmHg range and, therefore, were slightly less severe that in previous single-dose or open-label studies. It is not known, however, if more severely affected patients will respond differently to droxidopa. Droxidopa appears to have a good safety profile. The overall incidence of adverse events was similar in the

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Fig. 3 Effect of treatment with droxidopa 430±18 mg (SEM) three times/daily for 1 week compared to placebo. Panel a shows the change in overall symptoms score (composite of the OHQ questionnaire, the primary outcome) from baseline (Base) to end of treatment (Rx) produced by placebo (gray bars) and droxidopa (black bars). Panel b shows the upright systolic blood pressure (SBP) at baseline (Base) and at the end of treatment (Rx) in both groups. Asterisks denote statistical significance. Error bars denote the standard error of the mean (SEM). Note the reduction in symptom burden and increase in upright SBP in the placebo group. Data from Kaufmann et al. [56••]

droxidopa and placebo groups (18.5 and 14.8 %, respectively), with a relatively low reported incidence of adverse events related to supine hypertension (4.9 versus 2.5 %). We would expect a higher incidence of supine hypertension when droxidopa is prescribed outside a controlled clinical trial, especially if physicians are not careful in making sure that the last dose no is given later than 5 h before bedtime. It is not clear if a thrice-daily dose is needed, or if twice-daily dosing would be sufficient as suggested by a European open-label study [55]. Based on trials to date, droxidopa was granted approval by the FDA with the expectation that post-marketing studies will be completed to show persistence of effect after chronic administration of droxidopa. The drug is expected to be available in the USA for clinical use in late 2014 (trade name, Northera®).

Summary and Conclusions Orthostatic hypotension is an important and common medical problem, particularly in the frail elderly with multiple comorbidities and polypharmacy. Hypertension is among the most

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common comorbidities associated with OH. Orthostatic hypotension is an independent risk factor for falls and overall mortality. Despite its importance, there is a paucity of treatment options for this condition. Midodrine was approved for the treatment of OH in 1996 based on an increase in upright BP, with the understanding that post-marketing studies would be forthcoming to determine the efficacy of droxidopa in improving symptoms and patients’ functional status. Only very recently have the trials been conducted and results are not yet published. It has taken nearly two decades to develop another drug for the treatment of OH; droxidopa is a prodrug that is converted into norepinephrine by the same enzyme (dopa-decarboxylase) that converts levodopa to dopamine. Droxidopa has been shown to reduce symptoms of OH and to increase upright BP over a 1-week treatment period. Approval for clinical use for neurogenic OH was granted in early 2014 with the understanding that further research be completed to show persistence of its beneficial effects during chronic use. Other progress made in the management of OH has derived from small studies in severely affected patients with primary forms of autonomic failure, using repurposing of already-approved drugs. Several drugs have shown to acutely increase upright BP and improve orthostatic symptoms, but it is not clear if these drugs will stand the scrutiny of a controlled clinical trial or lead to sustained efficacy. The challenges encountered during the development of droxidopa highlight the difficulties in performing research with this patient population. The goal of therapy for OH is only to provide symptomatic relief, to reduce orthostatic symptoms, and to improve functional status and quality of life. It is hoped that this will result in prevention of falls, but this has not been formally tested. There is no evidence that treatment, particularly pharmacotherapy, will reduce the increased mortality risk associated with OH. It is also important to note that reaching an arbitrary upright BP is not the main therapeutic goal for drug therapy of OH. It is important, therefore, never to use pressor agents unless the patient is planning to be upright. Pressor agents should never be given while the patient is supine; this will only induce pressure diuresis and ultimately produce a paradoxical worsening of OH. It is also important to consider that current therapeutic recommendations are based on research involving patients with severe OH due to neurodegenerative primary autonomic disorders. Orthostatic hypotension is far more common in the frail elderly with multiple comorbidities and polypharmacy, but therapeutic research in that patient population is more challenging and virtually non-existent. In the absence of evidence-based guidelines, it seems wiser to treat the frail elderly with OH by using the less aggressive approach that will improve symptoms and prevent falls. In these patients, it is even more important to remove offending factors than can worsen OH, emphasize physical countermeasures in its treatment, and, if needed, start

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pressor agents on an as-needed basis. Hypertension is a frequent comorbidity, and while its presence complicates the treatment of OH, stopping antihypertensive agents is not a solution. Evidence indicates that uncontrolled hypertension worsens OH likely due to pressure diuresis. Both hypertension (targeting initially the renin-angiotensin system) and OH (with countermeasures and as needed pressor agents) require therapeutic intervention. Acknowledgments Dr. Biaggioni is supported by the National Institutes of Health grants RO1 NS055670, PO1 HL56693, UL1 TR000445-06 (Clinical and Translational Science Award) and the Paden Dysautonomia Center.

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Compliance with Ethics Guidelines Conflict of Interest Dr. Biaggioni was a consultant for Chelsea Therapeutics, Inc. during the development of droxidopa.

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Human and Animal Rights and Informed Consent This article does not report any studies in human or animal subjects performed by the author.

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New developments in the management of neurogenic orthostatic hypotension.

Orthostatic hypotension (OH) is defined as a sustained reduction of ≥ 20 mmHg systolic blood pressure or ≥ 10 mmHg diastolic blood pressure upon stand...
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