Long-Term Safety of Droxidopa in Patients with Symptomatic

Journal of the American Society of Hypertension -(-) (2016) 1–8

Research Article Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension Stuart Isaacson, MDa,*, Steven Vernino, MD, PhDb, Adam Ziemann, MD, PhDc,1, Gerald J. Rowse, PhDc,1, Uwa Kalu, MD, MPH, MBAc, and William B. White, MD, FASHd aParkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA; bDepartment of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA; cLundbeck LLC, Deerﬁeld, IL, USA; and dDivision of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT 06032, USA Manuscript received May 13, 2016 and accepted July 18, 2016

Abstract

The long-term safety of droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Par- kinson disease, pure autonomic failure, multiple system atrophy, or nondiabetic autonomic neuropathy was evaluated in a phase 3, multinational, open-label study in patients who previously participated in a double-blind, placebo-controlled clinical trial of droxidopa. A total of 350 patients received droxidopa 100 to 600 mg three times daily. Mean duration of droxidopa exposure was 363 days (range, 2–1133 days). Rates of serious adverse events (AEs), cardiac-related AEs, and supine hypertension were 24%, 5%, and 5%, respectively. Most AEs, including those of a cardiovascular nature, were not attributed by investigators to droxidopa. In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well tolerated during long-term use. J Am Soc Hypertens 2016;-(-):1–8. Ó 2016 The Authors. Published by Elsevier Inc. on behalf of American Society of Hypertension. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Keyword: Supine hypertension.

Introduction Conflict of interest: S.I. has received compensation from Lund- Neurogenic orthostatic hypotension (nOH) refers to beck LLC for consulting, speaking, and research activities. S.V. decreased blood pressure (BP) during head-up posture has received personal compensation from Lundbeck for advisory board and speaker bureau activities, consulting fees from Athena change (ie, standing or head-up tilt) resulting from auto- Diagnostics (Quest), and compensation as an associate editor of nomic failure. Failure of the sympathetic baroreflex results JAMA Neurology. U.K. is an employee of Lundbeck, which in inadequate norepinephrine release from sympathetic 1 funded this study; A.Z. and G.J.R. were Lundbeck employees at nerves innervating the blood vessels and heart. Autonomic the time of contribution. W.B.W. is a safety consultant for Lund- failure occurs in several central and peripheral neurologic beck LLC. No author received compensation for preparation or disorders, including Parkinson disease (PD), multiple sys- writing of this manuscript. tem atrophy (MSA), pure autonomic failure, and peripheral Financial support for research conduct and manuscript prepara- autonomic neuropathy.1,2 Estimates suggest that nOH is tion was provided by Lundbeck LLC. Lundbeck participated in present in 37% to 58% of patients with PD, 75% of patients study design; data analysis and interpretation; and the decision with MSA, and 100% of patients with pure autonomic fail- to submit the article for publication. ure.3 Orthostatic hypotension is associated with significant *Corresponding author: Stuart Isaacson, MD, Parkinson’s Dis- 4 ease and Movement Disorders Center of Boca Raton, 951 NW morbidity and mortality ; patients with nOH have an 13th Street, Bldg 5-E, Boca Raton, FL 33486, USA. Tel: þ1- increased risk of cardiovascular complications as well 561-392-1818; Fax: þ1-561-392-8989. (eg, heart failure, atrial fibrillation), and many have coexist- E-mail: [email protected] ing cardiovascular comorbidities (eg, hypertension, cardiac, 1 At the time the study was conducted and analyzed. or cerebrovascular conditions).4,5

1933-1711/$ - see front matter Ó 2016 The Authors. Published by Elsevier Inc. on behalf of American Society of Hypertension. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jash.2016.07.010 2 S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8

Droxidopa is an oral norepinephrine prodrug approved in Treatments the United States for the treatment of symptomatic nOH in patients with primary autonomic failure (PD, MSA, pure Droxidopa was administered at doses of 100 to 600 mg autonomic failure), dopamine b-hydroxylase deficiency, in 100-mg increments taken three times daily (TID); doses or nondiabetic autonomic neuropathy (NDAN).6 In short- were taken upon waking and at approximately 4-hour inter- term phase 3 trials, droxidopa significantly improved the vals to allow the last dose to be taken in the late afternoon hallmark symptoms of nOH (eg, orthostatic dizziness, and early enough before bedtime to minimize the risk of lightheadedness, or the ‘‘feeling like you are about to black hypertension during sleep (ie, supine hypertension). Pa- out’’), with patients reporting improved symptom severity tients received individualized doses that had been identified and impact on daily activities compared with placebo.7–9 during the titration period of a previous study, with some Droxidopa also increased standing systolic BP (SBP) in exceptions: all patients who entered the present study these patients.9,10 Short-term treatment with droxidopa from the 8- to 10-week double-blind study underwent was well tolerated in these studies, and most adverse events dose titration in the present study. At the discretion of (AEs) were mild or moderate in severity.7–9 The incidence the treating investigator physician, droxidopa doses could of supine hypertension, defined as SBP >180 mm Hg, be adjusted up or down in single steps for efficacy or ranged from 5% to 14%. Rates of other cardiovascular safety. Dose escalation was stopped if the patient had sus- > > events were low (eg, coronary artery disease, hypertension tained SBP 180 mm Hg or DBP 110 mm Hg in the su- [0%–8%]). pine (or semirecumbent) position was unable to tolerate Previous trials evaluated the efficacy and safety of drox- side effects believed to be related to the study drug or idopa over relatively short treatment durations of 1–2 and reached the maximum dose of droxidopa (600 mg TID; 8–10 weeks.7–9 The objective of the present study was to 1800 mg/d). evaluate the long-term safety of droxidopa for the treatment Scheduled assessments were conducted at months 1 and of symptomatic nOH based on frequency and type of AEs, 3, and every 3 months thereafter. Vasoconstricting agents BP and heart rate, and laboratory findings. (eg, ephedrine, dihydroergotamine, midodrine), tryptamine- based drugs (triptans; eg, sumatriptan), cyclopropane or halogen-containing inhalational anesthetics (eg, halothane), Methods catecholamine-containing preparations (eg, isoproterenol This was a phase 3, multinational, multicenter, open- [isoprenaline]), nonselective monoamine oxidase inhibi- label study in ambulatory patients with symptomatic nOH tors, long-acting antihypertensives, and ergotamine deriva- that assessed the long-term safety of droxidopa tives (except medications for PD) were prohibited during (ClinicalTrials.gov identifier, NCT01132326). Patients the study. Fludrocortisone was permitted, as were all PD entering this long-term study were required to have drugs. participated in a prior short-term,9 8- to 10-week,8,10 or 11,12 1-year double-blind, placebo-controlled droxidopa Assessments trial. This long-term, open-label study was conducted between February 2009 and October 2012. AEs, vital signs, and laboratory testing results were recorded at each clinic visit. Investigators classified AEs by Patients severity after obtaining the patient’s medical history. Labo- ratory testing included hematology, chemistry, and urinaly- Eligible patients were 18 years of age with symptom- sis; women of childbearing potential underwent a atic nOH (defined as a 20-mm Hg reduction in SBP on pregnancy test at each study visit. Vital sign assessment standing) associated with PD, MSA, pure autonomic fail- included BP (measured using the same calibrated equip- ure, or NDAN. Key exclusion criteria included use of vaso- ment at each visit), heart rate, temperature, and weight. constricting agents or long-acting antihypertensive medications, uncontrolled cardiac arrhythmias, a history Data Analyses of myocardial infarction within the past 2 years, current un- stable angina, uncompensated congestive heart failure All patients who received at least 1 dose of droxidopa (New York Heart Association Class III or IV), or diabetic were evaluated for safety. Continuous variables were sum- autonomic neuropathy. Patients with sustained severe hy- marized descriptively; frequencies and percentages were pertension (defined as SBP 180 mm Hg or diastolic BP calculated for categorical variables. In comparisons with [DBP] 110 mm Hg) were also excluded. To assess for baseline, baseline values reflect evaluations performed the presence of severe hypertension, BP was measured in before the first dose of study treatment in a short-term, dou- a supine (ie, semirecumbent; head and torso elevated ble-blind study unless the last visit in these studies occurred approximately 30-degrees from horizontal) or seated posi- >1 month before the start of the present study; all patients tion at three consecutive measurements within 1 hour. were off study drug at the time of baseline evaluations. S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8 3

Results Table 2 Selected concomitant medication use* (safety population, Patients and Treatment N ¼ 350) A total of 350 patients, enrolled at 111 centers in 7 coun- Anatomical Therapeutic Chemical Class n (%) tries, were included in the safety analysis. The mean age Dopa and dopa derivativesy 234 (66.9) z was 66 years, and most patients were men and white Mineralocorticoids 118 (33.7) (Table 1). Levodopa and dopa decarboxylase inhibitors Monoamine oxidase B inhibitors 87 (24.9) (carbidopa or benserazide combinations), with or without Dopamine agonists 78 (22.3) catechol-O-methyl transferase inhibitors (entacapone), Beta blocking agents, selective 14 (4.0) were used by 66.9% of patients (n ¼ 234/350; Table 2). Angiotensin-converting enzyme inhibitors, plain 10 (2.9) Dihydropyridine derivatives 9 (2.6) Monoamine oxidase B inhibitors or dopamine agonists ¼ ¼ Imidazoline receptor agonists 9 (2.6) were used by 24.9% (n 87/350) and 22.3% (n 78/ Organic nitrates 7 (2.0) 350) of patients, respectively. Fludrocortisone or fludrocor- Beta blocking agentsx 5 (1.4) tisone acetate was used by 33.7% patients. Short-acting an- Alpha and beta blocking agents 3 (0.9) tihypertensives of various drug classes were used by 0.3%– Thiazides, plain 3 (0.9) 4.0% of the study population. The most common reason for Angiotensin II antagonists, plain 1 (0.3) noncompletion of the study (36.7% of the total population) Beta blocking agents, nonselective 1 (0.3) was the transition of patients to a compassionate-use access Beta blocking agents (selective) and thiazides 1 (0.3) Table 1 * Concomitant medications include all medications taken during Demographics and baseline* characteristics (safety population, the study, including those started before but ongoing at first dose. If N ¼ 350) a patient had multiple occurrences of a medication, the patient is presented only once in the respective patient count. Medications n (%) are coded using the World Health Organization Drug dictionary. y Age, y Includes levodopa and dopa decarboxylase inhibitors (carbi- Mean (SD) 65.9 (15.16) dopa or benserazide combinations), with or without catechol-O- Range 18–90 methyl transferase inhibitors (entacapone). z Sex, n (%) Fludrocortisone or fludrocortisone acetate. x Male 214 (61.1) Route of administration not specified. Female 136 (38.9) Race/ethnicity, n (%) White 337 (96.3) Hispanic/Latino 7 (2.0) program; this program was available to patients at non-US Black/African American 4 (1.1) sites after the study was terminated in the European Union Asian 2 (0.6) and Canada. Other reasons for study discontinuation Primary clinical diagnosis, n (%) included withdrawal of consent (18.8%), AEs (17.0%), Parkinson disease 232 (66.3) and lack of efficacy (11.5%; Figure 1). Pure autonomic failure 68 (19.4) The mean duration of exposure to droxidopa during the Multiple system atrophy 33 (9.4) study was 362.6 days (median, 265 days; range, 2 to Nondiabetic autonomic 8 (2.3) 1133 days). The mean prescribed daily dose was neuropathy 419.8 mg TID (median, 409.1 mg TID). The most Other 7 (2.0) commonly administered dose of droxidopa was 600 mg Missing 2 (0.6) TID (42.3%, n ¼ 148/350), while 14.3%, 16.9%, and Seated systolic blood pressure, mm Hg Mean (SD) 121.97 (23.49) 15.7% of patients received 300, 400, or 500 mg TID, Range 56–208 respectively. Seated diastolic blood pressure, mm Hg Mean (SD) 72.47 (11.98) Range 40–111 Safety Heart rate, bpm Mean (SD) 71.33 (10.10) AEs were reported by 75.1% of patients (n ¼ 263/350; Range 41–109 Table 3). The most frequently reported AEs were falls (23.4%), urinary tract infection (13.4%), headache SD, standard deviation. * Long-term, open-label study baseline values reflect evalua- (12.0%), syncope (12.0%), and dizziness (9.7%). The ma- tions performed before the first dose of study treatment in a jority (92.3%) of AEs were mild or moderate in severity, short-term, double-blind study unless the last visit in these studies and most of the common AEs (ie, falls, urinary tract infec- occurred >1 month before the start of the present study; all pa- tion, and syncope) were reported by investigator physicians tients were off study drug at the time of baseline evaluations. to be manifestations of the underlying diseases (nOH, PD, 4 S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8

50 Completed per protocol: n=132 Did not complete per protocol: n=218

40 36.7

18.8 20 17.0 Patients, % 11.5 10 7.8 4.6 2.3 1.4

0 a b c

Death Other (n=5) (n=3)

(n=37) (n=25) (n=17) Adverse event Lack of efficacy (n=41) Lost to follow-up (n=10) (n=80) Consent withdrawn Investigator decision

Early study termination

Figure 1. Reasons for not completing study per protocol: aPatients discontinued the current long-term, open-label study when the study was transitioned to a compassionate-use access program in the European Union and Canada. bPatient withdrew consent, n ¼ 40; care- giver withdrew consent, n ¼ 1. cProtocol violation, declining health, and pregnancy (n ¼ 1 each).

MSA) rather than side effects of study medication. Most for 13.4% of patients (n ¼ 47/350). There were four discon- AEs (66.9%; n ¼ 234/263) resolved and required no change tinuations due to a hypertension-related diagnosis. to dose of study drug (77.1%, n ¼ 249/263). Dosing Serious AEs (SAEs) were experienced by 23.7% of pa- changes because of an AE included dose decrease for tients (n ¼ 83/350; Table 4); most SAEs were judged to 9.4% of patients (n ¼ 33/263) and dose interruption (but not discontinuation) for 10.3% of patients (n ¼ 36/263). AEs leading to discontinuation of study drug were reported Table 4 Serious adverse events reported by 0.9% of patients (safety population, N ¼ 350) Preferred Term* Patients, n (%) Table 3 Most commonly reported (5% of patients) adverse events (safety Any serious adverse event 83 (23.7) population, N ¼ 350) Syncope 10 (2.9) Pneumonia 7 (2.0) Preferred Term* n (%) Dehydration 7 (2.0) Fall 82 (23.4) Respiratory failure 4 (1.1) Gastrointestinal disorders 77 (22.0) Fall 4 (1.1) Urinary tract infection 47 (13.4) Transient ischemic attack 3 (0.9) Headache 42 (12.0) Sepsis 3 (0.9) Syncope 42 (12.0) Urinary tract infection 3 (0.9) Dizziness 34 (9.7) Hip fracture 3 (0.9) Fatigue 28 (8.0) Skin laceration 3 (0.9) Nausea 23 (6.6) Orthostatic hypotension 3 (0.9) Asthenia 23 (6.6) Aspiration 3 (0.9) Back pain 20 (5.7) Pneumonia aspiration 3 (0.9) Contusion 18 (5.1) Asthenia 3 (0.9) * Medical Dictionary for Regulatory Activities, version 10.1. * Medical Dictionary for Regulatory Activities, version 10.1. S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8 5

Table 5 Fatal serious adverse events in the study17 Age Sex Primary Preferred Term Dose (TID) at Study Day*/ Severity Diagnosis Time of Event, mg Duration 61 M MSA Respiratory failure 600 mg 598/3 Severe 57 M MSA Carotid artery thrombosis 600 mg 146/1 Severe 56 F MSA Circulatory collapse 500 mg 128/1 Moderate 62 M Pure autonomic Myocardial infarctiony 600 mg 550/1 Severe failure 53 M MSA MSA 600 mg 777/1 Severe 75 M NDAN Myocardial infarction 400 mg 363/1 Severe 61 F PD Respiratory failure 600 mg 1033/1 Severe 70 F MSA Acute respiratory failure 600 mg 443/5 Severe 73 M MSA Subdural hemorrhage 600 mg NDz/ND Severe 78 M PD Unknown causex 600 mg 439/ND ND 79 M MSA Sepsis 800 mg/dk 453/20 Severe 80 M PD Cardiorespiratory arrest 600 mg 37/2 Severe 79 M PD Pneumonia aspiration 600 mg 735/2 Severe 83 F PD Respiratory failure 400 mg, 100 days before 189/1 Severe respiratory failure 78 M PD Cardiorespiratory arrest{ 200 mg 104/1 Severe 85 M PD Respiratory arrest 600 mg 549/9 Severe 83 F PD Cardiac arrest 600 mg 530/1 Severe 62 M PD Urosepsisx,# 600 mg 500/1 ND 55 F MSA Brain edema 500 mg 51/5 Severe 60 F MSA Pneumonia 300 mg 169/17 Severe F, female; M, male; MSA, multiple system atrophy; ND, not determined; NDAN, nondiabetic autonomic neuropathy; PD, Parkinson disease; TID, 3 times daily. * Study day equals (day of onset of adverse event minus first day of treatment) plus 1. y Patient had a history of myocardial infarction/coronary heart disease and angina (all >2 years before study entry). z Patient took doses of 200 mg, 200 mg, then 400 mg droxidopa daily. x Patient death noted in study follow-up listing. k Patient did not have a recorded start date for the adverse event leading to death. { Patient had a history of incomplete bundle branch block, paroxysmal atrial fibrillation, and tachycardia. # Patient experienced a fatal event of urosepsis 23 days after discontinuation of study drug because of a serious adverse event of dehydration. be related to the underlying neurogenic diseases. The most There were 20 deaths during the study (Table 5). Nearly common SAEs were syncope (2.9%), pneumonia (2.0%), half of these deaths (n ¼ 9/20; 45.0%) occurred in patients and dehydration (2.0%). The rates of SAEs were highest with a diagnosis of MSA, and 60.0% of deaths (n ¼ 12/20) in patients with a primary diagnosis of MSA (45.5%) were associated with progression of disease, respiratory compared with those with PD (25.0%) or pure autonomic failure, or infection. The cause of one death was unknown. failure (8.8%). There were 35 discontinuations due to The remaining deaths (n ¼ 7/20; 35.0%) were reported to SAEs. have cardiovascular causes. Three patients with fatal car- Nineteen patients (5.4%) reported 25 cardiac-related diovascular SAEs had a medical history of cardiovascular AEs; 10 events were mild, 9 were moderate, and 6 were conditions. One fatal SAE (myocardial infarction) occurred severe. The severe cardiac-related AEs included atrial in a 62-year-old patient with pure autonomic failure after fibrillation (n ¼ 1), cardiorespiratory arrest (n ¼ 2), approximately 18 months of treatment. This patient had a myocardial infarction (n ¼ 2), and cardiac arrest (n ¼ 1). history of myocardial infarction, coronary artery disease, Cardiac-related AEs reported by >1 patient were atrial and angina (all >2 years before study entry), and the fibrillation (5 patients [1.4%]) and atrial flutter, brady- SAE was assessed by the investigator as not related to study cardia, cardiorespiratory arrest, myocardial infarction, and drug (Table 5). The duration of exposure to droxidopa in palpitations (2 patients [0.6%] each). Eleven cardiac- the present study at the time of the fatal events ranged related AEs were considered SAEs. The patient who expe- from 37 to 777 days (median, 439 days). There was no clus- rienced atrial flutter had a medical history of atrial tering of fatal events around the initiation of droxidopa. fibrillation. Two fatal events (pneumonia and myocardial infarction) 6 S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8

160 SBP DBP

140

120

100

80 Mean (SD) Blood Pressure, mmHg

BL 1 3 6 9 12 15 18 21 24 n= 350 321 308 253 188 158 129 105 80 44 Month

Figure 2. Time course of mean (SD) SBP and DBP. BL, baseline; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation. were designated by local site investigators as possibly months 12, 18, and 24 were 1 (9.8), 3 (11.5) bpm, and related to droxidopa. 0 (8.9) beats/min, respectively.

Vital Signs Laboratory Findings Laboratory values showed no trends or consistent Blood Pressure changes from baseline that were considered to be clinically SBP and DBP were recorded at each study visit in the signiﬁcant. Fifty-two patients (14.9%) had a total of 158 seated or supine (ie, semirecumbent) position. At baseline, AEs related to abnormal laboratory parameters. The most the mean (SD) SBP was 122 (23.5) mm Hg and the mean frequently reported laboratory-related AEs were decreased (SD) DBP was 72 (11.9) mm Hg. Generally, mean changes weight (3.4%), increased blood creatinine (3.1%), white from baseline in both SBP and DBP were small at most blood cells in urine (2.3%), increased blood creatine phos- time points (Figure 2). There were 17 patients (4.9%) phokinase (2.0%), and increased blood urea (2.0%). Except with 21 AEs of hypertension, and 7 patients (2.0%) with for one severe AE of hypoglycemia that occurred in a pa- 8 reported instances of increased BP. The rates of SBPs tient with diabetes using insulin, all AEs related to >180 mm Hg ranged from 0.6% (month 3) to 2.3% (month abnormal laboratory parameters were considered mild or 24). No patient had a DBP >120 mm Hg during the study. moderate in severity by the investigators.

Discussion Heart Rate At baseline, the mean (SD) heart rate was 71 (10.1) Previous studies of the synthetic norepinephrine prodrug beats/min. Mean changes from baseline in heart rate at droxidopa in patients with symptomatic nOH have S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8 7 demonstrated the drug to be effective and well tolerated in progressive neurodegenerative disorder that increased the short-term clinical trials. The present study extends our risk of developing a comorbid health condition over time.4,5 knowledge of the safety of long-term use of droxidopa to A limitation of this analysis is confounding by the open- treat patients with symptomatic nOH secondary to auto- label nature of the study design. Although all patients nomic failure in PD, pure autonomic failure, MSA, and included this open-label extension study entered from NDAN. Only 7% of the study population discontinued earlier double-blind, placebo-controlled trials of droxidopa, because of a lack of efficacy, suggesting durability of effi- the potential for bias associated with the open-label trial cacy of droxidopa in these patients. design includes patient recruitment or retention issues There were 20 deaths over the course of this study (eg, patients may be more likely to continue in an open- (5.7%), 7 of which were related to cardiovascular AEs label trial because receipt of active treatment is assured, (carotid artery thrombosis [n ¼ 1], circulatory collapse and the studies usually entail less complex treatment regi- [n ¼ 1], myocardial infarction [n ¼ 2], cardiorespiratory ar- mens and study assessment schedules than a double-blind rest [n ¼ 2], and cardiac arrest [n ¼ 1]). Although patients study), psychological effects (from knowledge of treatment with nOH are at increased risk of cardiovascular complica- assignment), and AEs reporting (due to patient/investigator tions,5 the incidence of cardiovascular AEs was relatively awareness).15,16 However, an open-label study can comple- low (5.4%) in this study. Many patients with primary auto- ment results identified in double-blind trials15 and may be nomic failure have both orthostatic hypotension and supine considered a relevant indicator of treatment effects consis- hypertension, which can be exacerbated by medications tent with those that would be observed in normal clinical used to treat orthostatic hypotension.13,14 In this study, practice.16 however, AEs of hypertension and increased BP, measured In conclusion, droxidopa was well tolerated during long- in a seated or supine (ie, semirecumbent) position, were re- term use in this long-term, open-label study in patients with ported for 4.9% and 2.0% of patients, respectively. When symptomatic nOH associated with PD, MSA, pure auto- compared with rates of cardiac AEs in reports of short- nomic failure, or NDAN. Most AEs, including cardiac term clinical trials,7–9 the risk of cardiac AEs did not AEs, were mild or moderate in severity; long-term use of appear to increase with longer exposure to droxidopa, and droxidopa did not appear to be associated with increased long-term droxidopa did not appear to be associated with risk of cardiovascular-related AEs or increased incidence an increased risk of cardiac AEs in this population. Howev- of laboratory abnormalities. er, the enrollment criteria excluded patients with severe cardiovascular disease, and those with cardiovascular disease Acknowledgments represented only a minority of patients that continued into this long-term study. Thus, it is difficult to generalize The authors received editorial assistance from CHC these safety results to patients with preexisting cardiovascu- Group (North Wales, PA), which was supported by Lund- lar disorders. Furthermore, the study population included a beck LLC. small number of patients with NDAN (n ¼ 8) and no patients with dopamine b-hydroxylase deficiency, which limits conclusions that can be drawn about droxidopa car- References diovascular safety in patients with nOH associated with these diagnoses. 1. Freeman R, Wieling W, Axelrod FB, Benditt DG, In the current long-term droxidopa treatment study, no Benarroch E, Biaggioni I, et al. Consensus statement new safety concerns were identified, and safety results on the definition of orthostatic hypotension, neurally were similar to those observed in short-term phase 3 effi- mediated syncope and the postural tachycardia syn- cacy studies.7–9 In two previous trials, AEs were reported drome. Clin Auton Res 2011;21(2):69–72. by 58.6% and 82.0% of patients,7,8 with lower rates 2. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypo- observed during the open-label dose-escalation and tension: a pathophysiological approach. Circulation double-blind treatment phases of a third trial (38.0% and 2009;119(1):139–46. 18.5%, respectively).9 Discontinuation due to an AE was 3. Metzler M, Duerr S, Granata R, Krismer F, reported for 4.9% to 12.4% of patients.7–9 As expected, Robertson D, Wenning GK. Neurogenic orthostatic hy- overall rates of AEs and discontinuations due to AEs potension: pathophysiology, evaluation, and manage- were higher (75.1% and 13.4%, respectively) in the current ment. J Neurol 2013;260(9):2212–9. study given the longer duration of follow-up compared with 4. Angelousi A, Girerd N, Benetos A, Frimat L, Gautier S, the short-term trials (362.6 days vs. 1–2 and 8–10 weeks). Weryha G, et al. Association between orthostatic hypo- A high discontinuation rate introduced the possibility of tension and cardiovascular risk, cerebrovascular risk, retention bias and is a major limitation of this study. The cognitive decline and falls as well as overall mortality: discontinuation rate may have been influenced by patients’ a systematic review and meta-analysis. J Hypertens overall health status. Many patients in this trial had a 2014;32(8):1562–71. discussion 71. 8 S. Isaacson et al. / Journal of the American Society of Hypertension -(-) (2016) 1–8

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