Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension
2017; Elsevier BV; Volume: 119; Issue: 7 Linguagem: Inglês
10.1016/j.amjcard.2016.11.066
ISSN1879-1913
AutoresWilliam B. White, Robert A. Hauser, Gerald J. Rowse, Adam Ziemann, L. Arthur Hewitt,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoThe norepinephrine prodrug droxidopa improves symptoms of neurogenic orthostatic hypotension, a condition that is associated with diseases of neurogenic autonomic failure (e.g., Parkinson disease, multiple system atrophy, pure autonomic failure). These conditions are more prevalent in older patients who also have cardiovascular co-morbidities. Hence, we evaluated the cardiovascular safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension who participated in randomized controlled studies (short-term studies of 1 to 2 weeks and an intermediate 8- to 10-week study) and long-term open-label studies. Rates of cardiovascular adverse events (AEs) for patients treated with droxidopa were 4.4% in the intermediate study and 10.8% in the long-term open-label studies. Adjusting for exposure time, cardiovascular AE rates were 0.30 events/patient-year in the short-term and intermediate studies and 0.15 events/patient-year in the long-term open-label studies. The incidence of treatment discontinuation due to blood pressure–related events was approximately 2.5%. Among patients with a history of cardiac disorders at baseline, the rates of cardiovascular-related and blood pressure–related AEs were nominally higher with droxidopa compared to placebo. Most of these events were minor atrial arrhythmias; none were major adverse cardiovascular events or deaths. In conclusion, small increases in cardiovascular AEs were observed with droxidopa compared to placebo; this was most evident in patients with preexisting cardiac disorders. The norepinephrine prodrug droxidopa improves symptoms of neurogenic orthostatic hypotension, a condition that is associated with diseases of neurogenic autonomic failure (e.g., Parkinson disease, multiple system atrophy, pure autonomic failure). These conditions are more prevalent in older patients who also have cardiovascular co-morbidities. Hence, we evaluated the cardiovascular safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension who participated in randomized controlled studies (short-term studies of 1 to 2 weeks and an intermediate 8- to 10-week study) and long-term open-label studies. Rates of cardiovascular adverse events (AEs) for patients treated with droxidopa were 4.4% in the intermediate study and 10.8% in the long-term open-label studies. Adjusting for exposure time, cardiovascular AE rates were 0.30 events/patient-year in the short-term and intermediate studies and 0.15 events/patient-year in the long-term open-label studies. The incidence of treatment discontinuation due to blood pressure–related events was approximately 2.5%. Among patients with a history of cardiac disorders at baseline, the rates of cardiovascular-related and blood pressure–related AEs were nominally higher with droxidopa compared to placebo. Most of these events were minor atrial arrhythmias; none were major adverse cardiovascular events or deaths. In conclusion, small increases in cardiovascular AEs were observed with droxidopa compared to placebo; this was most evident in patients with preexisting cardiac disorders. Neurogenic orthostatic hypotension (nOH) is caused by loss of the noradrenergic baroreceptor reflex, which can arise from dysfunction of central autonomic pathways or peripheral autonomic fibers caused by primary autonomic failure or other neuropathic conditions.1Benarroch E.E. The arterial baroreflex: functional organization and involvement in neurologic disease.Neurology. 2008; 71: 1733-1738Crossref PubMed Scopus (133) Google Scholar These neurogenic syndromes are associated with excessive cardiovascular (CV) morbidity and may also result in an increased risk of falls and related injuries.2Shaw B.H. Robinovitch S.N. Claydon V.E. Mechanisms underlying the relationships between cardiovascular dysfunction and fall susceptibility in older adults.Clin Auton Res. 2012; 22: 256Google Scholar Droxidopa, a synthetic oral prodrug of norepinephrine, is a novel therapy for symptomatic nOH caused by autonomic failure syndromes.3Biaggioni I. Freeman R. Mathias C.J. Low P. Hewitt L.A. Kaufmann H. Droxidopa 302 InvestigatorsRandomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.Hypertension. 2015; 65: 101-107Crossref PubMed Scopus (107) Google Scholar, 4Hauser R.A. Hewitt L.A. Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A).J Parkinsons Dis. 2014; 4: 57-65Crossref PubMed Scopus (73) Google Scholar, 5Hauser R.A. Isaacson S. Lisk J.P. Hewitt L.A. Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (NOH306B).Mov Disord. 2015; 30: 646-654Crossref PubMed Scopus (103) Google Scholar, 6Kaufmann H. Freeman R. Biaggioni I. Low P. Pedder S. Hewitt L.A. Mauney J. Feirtag M. Mathias C.J. NOH301 InvestigatorsDroxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.Neurology. 2014; 83: 328-335Crossref PubMed Scopus (194) Google Scholar In randomized, double-blind, placebo-controlled phase 3 trials of patients with nOH, droxidopa decreased nOH symptoms (dizziness, lightheadedness, feeling faint) and reduced the fall rate.7Hauser R.A. Heritier S. Rowse G.J. Hewitt L.A. Isaacson S.H. Droxidopa and reduced falls in a trial of Parkinson patients with neurogenic orthostatic hypotension.Clin Neuropharmacol. 2016; 39: 220-226Crossref PubMed Scopus (38) Google Scholar CV co-morbidities are common in patients with nOH,8Fagard R.H. De Cort P. Orthostatic hypotension is a more robust predictor of cardiovascular events than nighttime reverse dipping in elderly.Hypertension. 2010; 56: 56-61Crossref PubMed Scopus (102) Google Scholar, 9Maule S. Milazzo V. Maule M.M. Di Stefano C. Milan A. Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar and droxidopa increases norepinephrine levels and has the potential to increase supine blood pressure (BP).9Maule S. Milazzo V. Maule M.M. Di Stefano C. Milan A. Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar, 10Northera (droxidopa)Full Prescribing Information. Lundbeck NA Ltd, Deerfield, IL2014: 1-10Google Scholar Even without treatment for orthostatic hypotension, approximately 50% of patients with nOH with primary autonomic failure have supine hypertension,11Shannon J.R. Jordan J. Diedrich A. Pohar B. Black B.K. Robertson D. Biaggioni I. Sympathetically mediated hypertension in autonomic failure.Circulation. 2000; 101: 2710-2715Crossref PubMed Scopus (149) Google Scholar, 12Umehara T. Matsuno H. Toyoda C. Oka H. Clinical characteristics of supine hypertension in de novo Parkinson disease.Clin Auton Res. 2016; 26: 15-21Crossref PubMed Scopus (42) Google Scholar which can be associated with left ventricular hypertrophy or increased nocturnal pressure natriuresis.13Jordan J. Shannon J.R. Pohar B. Paranjape S.Y. Robertson D. Robertson R.M. Biaggioni I. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure.J Am Soc Nephrol. 1999; 10: 35-42Crossref PubMed Google Scholar, 14Vagaonescu T.D. Saadia D. Tuhrim S. Phillips R.A. Kaufmann H. Hypertensive cardiovascular damage in patients with primary autonomic failure.Lancet. 2000; 355: 725-726Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 15Milazzo V. Maule S. Di Stefano C. Tosello F. Totaro S. Veglio F. Milan A. Cardiac organ damage and arterial stiffness in autonomic failure: comparison with essential hypertension.Hypertension. 2015; 66: 1168-1175Crossref PubMed Scopus (24) Google Scholar Hence, we evaluated the CV safety of droxidopa in patients with symptomatic nOH who participated in controlled clinical trials and in the long-term open-label extension program of the drug. The CV safety of droxidopa was examined in an analysis of CV- and BP-related adverse events (AEs) reported in the phase 3 clinical development program for this orphan therapy. Data were derived from 3 randomized, placebo-controlled trials3Biaggioni I. Freeman R. Mathias C.J. Low P. Hewitt L.A. Kaufmann H. Droxidopa 302 InvestigatorsRandomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.Hypertension. 2015; 65: 101-107Crossref PubMed Scopus (107) Google Scholar, 4Hauser R.A. Hewitt L.A. Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A).J Parkinsons Dis. 2014; 4: 57-65Crossref PubMed Scopus (73) Google Scholar, 5Hauser R.A. Isaacson S. Lisk J.P. Hewitt L.A. Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (NOH306B).Mov Disord. 2015; 30: 646-654Crossref PubMed Scopus (103) Google Scholar, 6Kaufmann H. Freeman R. Biaggioni I. Low P. Pedder S. Hewitt L.A. Mauney J. Feirtag M. Mathias C.J. NOH301 InvestigatorsDroxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.Neurology. 2014; 83: 328-335Crossref PubMed Scopus (194) Google Scholar and 2 long-term open-label studies16Isaacson S. Shill H.A. Vernino S. Ziemann A. Rowse G.J. Safety and durability of effect with long-term, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH303).J Parkinsons Dis. 2016; 6: 751-759Crossref PubMed Scopus (25) Google Scholar, 17Isaacson S. Vernino S. Ziemann A. Rowse G.J. Kalu U. White W.B. Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension.J Am Soc Hypertens. 2016; 10: 755-762Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar and were grouped according to study design and treatment duration (short-term, intermediate [8 to 10 weeks] double-blind, or long-term open-label; Figure 1). The design of the 2 short-term pivotal studies3Biaggioni I. Freeman R. Mathias C.J. Low P. Hewitt L.A. Kaufmann H. Droxidopa 302 InvestigatorsRandomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.Hypertension. 2015; 65: 101-107Crossref PubMed Scopus (107) Google Scholar, 6Kaufmann H. Freeman R. Biaggioni I. Low P. Pedder S. Hewitt L.A. Mauney J. Feirtag M. Mathias C.J. NOH301 InvestigatorsDroxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.Neurology. 2014; 83: 328-335Crossref PubMed Scopus (194) Google Scholar approved (and advocated) by the US Food and Drug Administration identified patients who responded to open-label titration of droxidopa before randomization of these responders to 1 or 2 weeks of double-blind, placebo-controlled treatment. In the intermediate double-blind study,4Hauser R.A. Hewitt L.A. Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A).J Parkinsons Dis. 2014; 4: 57-65Crossref PubMed Scopus (73) Google Scholar, 5Hauser R.A. Isaacson S. Lisk J.P. Hewitt L.A. Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (NOH306B).Mov Disord. 2015; 30: 646-654Crossref PubMed Scopus (103) Google Scholar patients with Parkinson disease were randomized to dose titration of placebo or droxidopa followed by 8 weeks of stable dosing. In the 2 long-term studies,16Isaacson S. Shill H.A. Vernino S. Ziemann A. Rowse G.J. Safety and durability of effect with long-term, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH303).J Parkinsons Dis. 2016; 6: 751-759Crossref PubMed Scopus (25) Google Scholar, 17Isaacson S. Vernino S. Ziemann A. Rowse G.J. Kalu U. White W.B. Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension.J Am Soc Hypertens. 2016; 10: 755-762Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar mean exposure to droxidopa was 312 days (maximum exposure, 714 days) and 362 days (maximum exposure, 1,133 days), respectively. Doses of droxidopa used in the studies were titrated to effect and tolerability and ranged from 100 to 600 mg thrice daily. Duration of drug exposure was defined as the number of days from the first to the last dose of study drug (droxidopa or placebo) taken by the patient. All studies included adults diagnosed with symptomatic nOH, confirmed by a documented decrease of ≥20 mm Hg in systolic BP or ≥10 mm Hg in diastolic BP within 3 minutes after standing. Patients eligible for enrollment in the short-term and long-term studies had nOH associated with primary autonomic failure (Parkinson disease, multiple system atrophy, and pure autonomic failure), dopamine β-hydroxylase deficiency, or nondiabetic autonomic neuropathy, whereas patients eligible for enrollment in the intermediate double-blind study had nOH associated with Parkinson disease only. Patients in the long-term studies were required to have participated in one of the short-term studies or the intermediate double-blind study. Patients completing the 1-year long-term study16Isaacson S. Shill H.A. Vernino S. Ziemann A. Rowse G.J. Safety and durability of effect with long-term, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH303).J Parkinsons Dis. 2016; 6: 751-759Crossref PubMed Scopus (25) Google Scholar were also eligible to continue open-label droxidopa treatment in a separate long-term study.17Isaacson S. Vernino S. Ziemann A. Rowse G.J. Kalu U. White W.B. Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension.J Am Soc Hypertens. 2016; 10: 755-762Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Exclusion criteria for the studies were preexisting sustained severe hypertension (BP ≥180/110 mm Hg in the sitting position), clinically significant cardiac arrhythmias, myocardial infarction, current unstable angina, or uncompensated congestive heart failure (New York Heart Association Class III or IV). Vasoconstrictor agents or long-acting antihypertensive therapies were not allowed. Use of serotonin-norepinephrine reuptake inhibitors was excluded in all studies except the intermediate double-blind study. CV AEs occurring during treatment and serious AEs were identified using the system organ classes and preferred terms of the Medical Dictionary for Regulatory Activities (Supplementary Table 1). There was no formal CV adjudication process during droxidopa development. If a patient experienced multiple events that mapped to a single preferred term, the greatest severity was assigned for the applicable table. BP events included those classified as hypertension, hypertensive crisis, and increased BP. In the long-term open-label studies, terms of malignant hypertension and BP fluctuations were also recorded based on the information provided by the patients' physicians. The incidence rates of CV events were determined in the subgroups of patients with or without baseline CV conditions in the short-term and intermediate double-blind studies. Baseline CV conditions included arrhythmias, ischemic heart disease, hypertension, ventricular hypertrophy or cardiomegaly, aortic stenosis, valvular abnormalities, and congestive heart failure. Twelve-lead electrocardiograms were performed during double-blind treatment in the short-term studies, at baseline and during stable dosing in the intermediate double-blind study, and at each study visit in the long-term open-label studies. The electrocardiograms were evaluated for heart rate and QT, RR, PR, and QRS intervals. QT intervals were corrected for heart rate using Bazett's formula (QTcB) and Fridericia's formula (QTcF). The electrocardiogram parameters were tabulated by visit and by the frequency of QTcB or QTcF intervals ≥450, ≥480, and ≥500 ms. Changes from baseline in QTcB or QTcF were also categorized as ≥30 and ≥60 ms. CV- and BP-related AEs and electrocardiogram results in each study grouping were combined for analysis. AE incidence was adjusted for exposure to study drug expressed in events per patient-year. AEs that were treatment emergent, serious, and that led to treatment discontinuation were tabulated. Data were summarized using descriptive statistics. The baseline characteristics of the patients in the various studies are provided in Table 1. Parkinson disease was the primary diagnosis for about 40% of patients in the short-term study group, all patients in the intermediate double-blind study, and in 63% of patients in the long-term open-label studies (Table 1). Baseline CV morbidities were common in the studies, ranging from 34% to 70% of randomized patients (Table 2).Table 1Demographic and baseline characteristics of study populationsStudy GroupShort-Term Studies (Double-Blind Phase)IntermediateDouble-Blind StudyLong-TermOpen-Label StudiesCharacteristicPlacebo(n=132)Droxidopa(n=131)Placebo(n=108)Droxidopa(n=114)Droxidopa(N=422)Mean (SD) age, years60.0 (17.9)59.5 (16.0)72.4 (8.0)72.6 (7.5)65.3 (14.7)Men75 (57%)71 (54%)68 (63%)77 (68%)253 (60%)White race124 (94%)130 (99%)102 (94%)110 (97%)406 (96%)Primary clinical diagnosis Parkinson disease54 (41%)56 (43%)108 (100%)114 (100%)265 (63%) Multiple system atrophy25 (19%)31 (24%)Not applicableNot applicable55 (13%) Pure autonomic failure38 (29%)34 (26%)Not applicableNot applicable78 (19%) Dopamine β-hydroxylase deficiency1 (1%)0Not applicableNot applicable1 (0.2%) Non-diabetic autonomic neuropathy9 (7%)4 (3%)Not applicableNot applicable12 (3%) Other5 (4%)6 (5%)Not applicableNot applicable9 (2%) Missing00002 (0.5%) Open table in a new tab Table 2Prevalence of preexisting cardiovascular disorders in study groupsVariableShort-TermStudies(N=444)IntermediateDouble-Blind Studies(N=222)Total patients with preexisting cardiovascular condition∗Patients may have had multiple preexisting cardiovascular disorders and are included in each category. The following categories were not included in the analysis: procedures (eg, cardiac catheterizations, angiograms, tomography, echocardiograms) and cardiac murmurs.152 (34%)155 (70%)Arrhythmia80 (18%)155 (70%) Pacemaker placement27 (6%)12 (5%) Palpitations or atrial fibrillation16 (4%)17 (8%) Conduction system abnormalities†Not all conduction system abnormalities were associated with clinical arrhythmias.14 (3%)84 (38%) Bradycardia syndrome10 (2%)15 (7%) Tachycardia syndrome7 (2%)7 (3%) Unspecified arrhythmia6 (1%)22 (10%)Ischemic heart disease67 (15%)91 (41%) Coronary artery disease or angina41 (9%)41 (19%) Coronary artery bypass grafting, cardiac stents, or angioplasty16 (4%)21 (10%) Myocardial infarction10 (2%)11 (5%)Hypertension60 (14%)56 (25%)Cardiac valvular abnormalities16 (4%)31 (14%)Left ventricular hypertrophy3 (0.7%)10 (5%)Heart failure1 (0.2%)3 (1%)∗ Patients may have had multiple preexisting cardiovascular disorders and are included in each category. The following categories were not included in the analysis: procedures (eg, cardiac catheterizations, angiograms, tomography, echocardiograms) and cardiac murmurs.† Not all conduction system abnormalities were associated with clinical arrhythmias. Open table in a new tab There were no CV events reported after randomization to double-blind treatment with placebo or droxidopa in the short-term studies, and CV event rates were 4.4% on droxidopa in the intermediate double-blind study and 10.8% in the long-term open-label studies (Supplementary Table 2). Most of these events were minor atrial arrhythmias; none were major adverse CV events. Seven deaths (0.02 deaths/patient-year) occurred in the long-term open-label study group. Causes of death included sudden death, etiology unknown (n = 5), and myocardial infarction (n = 2) and occurred sporadically over 2 years. Exposure-adjusted rates of CV events/patient-year were calculated to account for different durations of drug exposure among the study groups (Figure 2 and Supplementary Table 2). No CV events were reported during the brief double-blind treatment in the short-term studies. In the intermediate double-blind study, among patients with a preexisting CV condition, those treated with droxidopa had 5 CV AEs compared to 2 CV AEs for patients receiving placebo; in patients without a history of CV disease, there was 1 CV event each for droxidopa and placebo (Figure 2). A total of 45 patients (12.9%) in the long-term open-label study had vascular AEs, and 19 patients (5.4%) had disorders of a cardiac nature (Supplementary Table 2), including 23 events that were serious in 22 patients (5.2%) and 14 events resulting in discontinuation of study participation. Atrial fibrillation was the most common treatment-emergent cardiac event during the study (4 events, 2 with hospitalization) occurring in only 4 patients (1.3%). CV AE rates adjusted for drug exposure were 0.30 events/patient-year in patients treated with droxidopa, compared to 0.11 events/patient-year in placebo recipients. The exposure-adjusted rate of CV AEs was 0.15 events/patient-year in the long-term open-label study group. Hypertension-related events are provided in Table 3. In all 3 study groups, hypertension and increased BP were the most frequently reported CV AEs, but the rate of discontinuations because of BP-related events was low (≤2.6%). No serious AEs due to hypertension were reported in the short-term study group. In the intermediate double-blind study, 1 serious event characterized as a hypertension exacerbation (peak BP was 178/72 mm Hg during an orthostatic standing test) was reported in the droxidopa group (0.9%). In the long-term open-label study group (n = 422), there were 6 serious events associated with hypertension or BP elevations (1.4%). These events occurred up to 321 days into the long-term study period and were characterized as either severe or accelerated hypertension and resulted in treatment in emergency department settings or hospitalization for treatment. There were no hypertension-related deaths or episodes of hypertension associated with target organ injury (e.g., heart failure or stroke).Table 3Blood pressure–related treatment-emergent adverse events and discontinuations by study groupEventShort-TermStudies (Double-Blind Phase)IntermediateDouble-Blind StudyLong-TermOpen-Label StudiesDroxidopa(n=131)Placebo(n=132)Droxidopa(n=114)Placebo(n=108)Droxidopa(N=422)PatientsEventsDCsPatientsEventsDCsPatientsEventsDCsPatientsEventsDCsPatientsEventsDCsHypertension2 (2%)200008 (7%)113 (3%)1 (0.9%)21 (0.9%)19 (5%)232 (0.5%)Blood pressure increased0000004 (4%)92 (2%)7 (7%)71 (0.9%)7 (2%)81 (0.2%)Systolic blood pressure increased0000001 (0.9%)101 (0.9%)10000Blood pressure fluctuation0000000000001 (0.2%)10Other0000000000004 (0.9)43 (0.7)DCs = discontinuations. Open table in a new tab DCs = discontinuations. During the short-term studies, increases in supine systolic BP above 160 mm Hg at all 3 measurements during the 10-minute supine period of an orthostatic standing test occurred in 9.9% of patients receiving droxidopa versus 6.1% of patients treated with placebo; increases above 180 mm Hg occurred in 3.1% versus 1.5% of patients, respectively; there were no increases above 200 mm Hg. In the intermediate study, increases above 160 mm Hg were reported in 28.9% versus 24.1% of patients in the droxidopa and placebo groups, respectively; increases above 180 mm Hg occurred in 7.9% and 4.6% of patients; and increases above 200 mm Hg occurred in 3.5% and 0.9% of patients, respectively. There were also no clinically important changes from baseline in QTcB or QTcF intervals or in categories of change in the corrected QT interval in any of the study groups (Supplementary Table 3). The present analysis evaluated the CV safety of droxidopa in patients with symptomatic nOH caused by Parkinson disease and other neurodegenerative diseases from controlled trials and open-label extension studies of the drug. The results showed low and comparable rates of CV events in patients receiving droxidopa and placebo. There were more events due to elevated BP or hypertension on droxidopa than placebo. Sparse but prespecified electrocardiogram assessments demonstrated no evidence of prolongation of the QT interval or other conduction abnormalities associated with droxidopa. After correction for exposure, CV event rates were modestly higher on droxidopa in patients with preexisting cardiac disorders. Patients with neurodegenerative diseases that cause autonomic instability and hypotension have increases in CV co-morbidities,2Shaw B.H. Robinovitch S.N. Claydon V.E. Mechanisms underlying the relationships between cardiovascular dysfunction and fall susceptibility in older adults.Clin Auton Res. 2012; 22: 256Google Scholar, 9Maule S. Milazzo V. Maule M.M. Di Stefano C. Milan A. Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar, 18Fedorowski A. Stavenow L. Hedblad B. Berglund G. Nilsson P.M. Melander O. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project).Eur Heart J. 2010; 31: 85-91Crossref PubMed Scopus (267) Google Scholar so it was not surprising that events accrued during the longer-term follow-up in this patient population. Few events were seen in the shorter-term clinical trials, due in part to the study design in which dose escalation was stopped if the patient developed sustained supine hypertension, was not able to tolerate side effects, or reached the maximum droxidopa dose.3Biaggioni I. Freeman R. Mathias C.J. Low P. Hewitt L.A. Kaufmann H. Droxidopa 302 InvestigatorsRandomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.Hypertension. 2015; 65: 101-107Crossref PubMed Scopus (107) Google Scholar, 4Hauser R.A. Hewitt L.A. Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A).J Parkinsons Dis. 2014; 4: 57-65Crossref PubMed Scopus (73) Google Scholar, 5Hauser R.A. Isaacson S. Lisk J.P. Hewitt L.A. Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (NOH306B).Mov Disord. 2015; 30: 646-654Crossref PubMed Scopus (103) Google Scholar, 6Kaufmann H. Freeman R. Biaggioni I. Low P. Pedder S. Hewitt L.A. Mauney J. Feirtag M. Mathias C.J. NOH301 InvestigatorsDroxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.Neurology. 2014; 83: 328-335Crossref PubMed Scopus (194) Google Scholar During the open-label droxidopa titration in all trials, AEs were mostly nonserious and due to asymptomatic supine hypertension. The design of the short-term studies used a rapid titration scheme to achieve increases in standing systolic BP within 5 to 7 days. Because many safety observations were recorded during initiation of treatment in the open-label dose-titration phase, a slower rate of dose titration during droxidopa dose optimization may be appropriate for patients with preexisting cardiac conditions. Although the presence of a preexisting cardiac disorder was associated with an increase in CV AEs during long-term treatment, event rates did not accelerate or appear cumulative during long-term droxidopa exposure. It is not clear whether there was causality between droxidopa and these events considering the relatively low rate (11%) and the known CV morbidity of the patient population. We acknowledge limitations to this analysis. The durations of the double-blind study phases were short, and although the open-label data are more robust, they lacked a placebo control or a comparator agent. However, longer term placebo-controlled trials would not be feasible in this patient population because of disease severity and symptoms associated with underlying clinical conditions. There are historical data on CV morbidity and mortality in patients with nOH, and our results are not much different from those reports.9Maule S. Milazzo V. Maule M.M. Di Stefano C. Milan A. Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension.Funct Neurol. 2012; 27: 101-106PubMed Google Scholar, 12Umehara T. Matsuno H. Toyoda C. Oka H. Clinical characteristics of supine hypertension in de novo Parkinson disease.Clin Auton Res. 2016; 26: 15-21Crossref PubMed Scopus (42) Google Scholar, 14Vagaonescu T.D. Saadia D. Tuhrim S. Phillips R.A. Kaufmann H. Hypertensive cardiovascular damage in patients with primary autonomic failure.Lancet. 2000; 355: 725-726Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 15Milazzo V. Maule S. Di Stefano C. Tosello F. Totaro S. Veglio F. Milan A. Cardiac organ damage and arterial stiffness in autonomic failure: comparison with essential hypertension.Hypertension. 2015; 66: 1168-1175Crossref PubMed Scopus (24) Google Scholar The absolute CV risk in our analysis would be considered reasonably low for a drug that is used in high CV risk populations.19Borer J.S. Pouleur H. Abadie E. Follath F. Wittes J. Pfeffer M.A. Pitt B. Zannad F. Cardiovascular safety of drugs not intended for cardiovascular use: need for a new conceptual basis for assessment and approval.Eur Heart J. 2007; 28: 1904-1909Crossref PubMed Scopus (20) Google Scholar In conclusion, there was a low incidence of CV events in patients with nOH on droxidopa. There were no imbalances in CV event rates with droxidopa compared to placebo, other than rates of hypertension, which is not an unexpected finding. The utility of droxidopa for the treatment of nOH includes improvement in both standing systolic BP accompanied by clinically important reductions in lightheadedness and dizziness and preliminary evidence that the drug reduces falls. These benefits are important to patients with nOH and we believe outweigh the CV risks calculated in our analysis. Of note, formal safety data do not exist for other pressor agents used for the treatment of nOH. Hence, we believe these data contribute to the ability of clinicians to more safely manage patients with nOH with this pressor agent. The authors would like to thank Katya Chernya, from Lundbeck LLC, who provided statistical support. The authors also received editorial assistance from CHC Group (North Wales, PA), supported by Lundbeck LLC. The funder of the original clinical trials used in this analysis was Chelsea Therapeutics, Inc. Dr. White serves on a droxidopa safety committee formed by Lundbeck LLC. Dr. Hauser has served as a consultant and advisory board member for Lundbeck Pharmaceuticals. Dr. Hewitt is an employee of Lundbeck, and Drs. Rowse and Ziemann were employees of Lundbeck when the analysis was conducted and this manuscript was written. The authors and the study sponsor participated in the original study designs, data analysis and interpretation, and drafting the manuscript and supported the decision to submit the manuscript for publication. Download .docx (.04 MB) Help with docx files Supplementary Table 1 Download .docx (.05 MB) Help with docx files Supplementary Table 2 Download .docx (.04 MB) Help with docx files Supplementary Table 3
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