The correlation of orthostatic hypotension in Parkinson disease with the disease course and severity and its impact on quality of life.

We investigated the correlation of orthostatic hypotension (OH) in Parkinson disease (PD) with the disease course and severity, and its possible impact on quality of life. 171 PD patients were recruited and divided into the PD-NOH (n = 91) and PD-OH groups (n = 80). Clinical data were collected. The severity and quality of life of PD patients were evaluated. The impact of disease severity was analyzed using logistic regression analysis. The ROC curve was plotted. There were significant differences (P < .05) between PD-NOH and PD-OH groups in terms of the disease course, non-motor symptoms (somnipathy), Hoehn&Yahr stage, LEDD score, RBDSQ score, PDQ-39 score, MMSE score, MoCA, MDS-UPDRS Part III scores during off- and on-periods, and NMSS score. Hoehn&Yahr stage (OR 4.950, 95% CI 1.516-16.157, P = .008) was closely associated with the risk of OH in PD. PDQ-39 score (OR 1.079, 95% CI 1.033-1.127, P = .001) in PD patients with OH further decreased. Patients with PD-OH experienced severe impairment in 4 dimensions of quality of life, including motor function, cognitive function, physical discomfort, and activities of daily living. Different clinical symptoms of PD-OH were positively correlated with PDQ39 subscales. The area under the ROC curve of the Hoehn&Yahr stage in predicting the occurrence of OH was 0.679 (95% CI 0.600-0.758), and that of the Hoehn&Yahr stage combined with levodopa equivalent dose, and MDS-UPDRS Part III score during off-period was 0.793 (95% CI 0.727-0.862). Higher Hoehn&Yahr stage is associated with increased risk of OH in PD patients, and deteriorated quality of life of PD patients. Patients with different OH symptoms are affected in different dimensions of their quality of life. The Hoehn & Yahr stage can independently predict the risk of OH in PD patients.

Exploring Cardiovascular Autonomic Function before and after Chronic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Blood pressure control in Parkinson's disease (PD) under subthalamic deep brain stimulation (STN-DBS) is influenced by several intertwined aspects, including autonomic failure and levodopa treatment. OBJECTIVE: To evaluate the effect of chronic STN-DBS, levodopa, and their combination on cardiovascular autonomic functions in PD. METHODS: We performed cardiovascular reflex tests (CRTs) before and 6-months after STN-DBS surgery in 20 PD patients (pre-DBS vs. post-DBS). CRTs were executed without and with medication (med-OFF vs. med-ON). RESULTS: CRT results and occurrence of neurogenic orthostatic hypotension (OH) did not differ between pre- and post-DBS studies in med-OFF condition. After levodopa intake, the BP decrease during HUTT was significantly greater compared to med-OFF, both at pre-DBS and post-DBS evaluation. Levodopa-induced OH was documented in 25% and 5% of patients in pre-DBS/med-ON and post-DBS/med-ON study. CONCLUSION: Chronic stimulation did not influence cardiovascular responses, while levodopa exerts a relevant hypotensive effect. The proportion of patients presenting levodopa-induced OH decreases after STN-DBS surgery.

A novel mechanism of idiopathic orthostatic hypotension and hypocatecholaminemia due to autoimmunity against aromatic l-Amino acid decarboxylase.

Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l-amino acid decarboxylase (AADC), which converts l-DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH.

Orthostatic hypotension in Parkinson's disease: Sit-to-stand vs. supine-to-stand protocol and clinical correlates.

BACKGROUND: Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking. METHODS: We investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated. RESULTS: Patients' mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring. CONCLUSIONS: The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH.

Progressive QTc prolongation and reduced heart rate variability in dementia with Lewy bodies compared to Alzheimer's disease.

INTRODUCTION: Autonomic dysfunction (AuD) is a significant clinical challenge in patients with Dementia with Lewy Bodies (DLB). Manifestations of AuD such as orthostatic hypotension (OH) is associated with falls and decreased quality of life. Cardiac autonomic denervation is an early phenomenon in DLB and a potential contributor to OH. This retrospective study was undertaken to explore whether routine ECG tracings could be used to identify signs of autonomic dysfunction in DLB. METHODS: 18 patients with DLB and 18 age-matched patients with Alzheimer's disease (AD) were included. ECGs and clinical data were analyzed retrospectively for heart rate variability (HRV) and QTc interval prolongation. RESULTS: During an average of 10 years observation time (first to last ECG recording), the QTc interval increased in the DLB group, but not in the AD group. HRV was significantly lower at end of follow-up in the DLB group than in the AD group. DLB patients with OH had greater QTc prolongation. CONCLUSION: Longitudinal ECG analysis indicates that signs of AuD in DLB are reflected on routine ECG tracings. If confirmed in larger cohorts, this could influence risk stratification and help direct preventive measures.

Impaired vestibular function associated with orthostatic hypotension in patients with multiple system atrophy.

BACKGROUND: Orthostatic hypotension (OH) is one of the most common symptoms in patients with multiple system atrophy (MSA). Vestibular system plays an important role in blood pressure regulation during orthostatic challenges through vestibular-sympathetic reflex. The current study aimed to investigate the relationship between vestibular function and OH in patients with MSA. METHODS: Participants with MSA, including 20 with OH (mean age, 57.55 ± 8.44 years; 7 females) and 15 without OH (mean age, 59.00 ± 8.12 years; 2 females) and 18 healthy controls (mean age, 59.03 ± 6.44 years; 8 females) were enrolled. Cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) tests were conducted to evaluate vestibular function. RESULTS: Patients with MSA presented with significantly higher rate of absent cVEMPs (57.1% vs 11.1%, p = 0.001) and oVEMPs (25.7% vs 0, p = 0.021) than controls. MSA patients with OH showed more absent cVEMPs (75.0% vs 11.1%, Bonferroni corrected p < 0.001) and oVEMPs (40.0% vs 0, Bonferroni corrected p = 0.003) than controls. Patients with OH also showed higher rate of absent cVEMPs than those without OH (33.3%, Bonferroni corrected p = 0.014). CONCLUSIONS: Our results demonstrated that impairment of vestibular function was associated with MSA, particularly in those with OH. Absent VEMPs may be a potential marker for MSA severity. Our findings suggest that impaired vestibular function is involved in OH development and may serve as an intervention target.

Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association.

Although orthostatic hypotension (OH) has long been recognized as a manifestation of autonomic dysfunction, a growing body of literature has identified OH as a common comorbidity of hypertension. This connection is complex, related to pathophysiology in blood pressure regulation and the manner by which OH is derived as the difference between 2 blood pressure measurements. While traditional therapeutic approaches to OH among patients with neurodegenerative disorders focus on increasing upright blood pressure to prevent cerebral hypoperfusion, the management of OH among patients with hypertension is more nuanced; resting hypertension is itself associated with adverse outcomes among these patients. Although there is substantial evidence that intensive blood pressure treatment does not cause OH in the majority of patients with essential hypertension, some classes of antihypertensive agents may unmask OH in patients with an underlying autonomic impairment. Practical steps to manage OH among adults with hypertension start with (1) a thorough characterization of its patterns, triggers, and cause; (2) review and removal of aggravating factors (often pharmacological agents not related to hypertension treatment); (3) optimization of an antihypertensive regimen; and (4) adoption of a tailored treatment strategy that avoids exacerbating hypertension. These strategies include countermaneuvers and short-acting vasoactive agents (midodrine, droxidopa). Ultimately, further research is needed on the epidemiology of OH, the impact of hypertension treatment on OH, approaches to the screening and diagnosis of OH, and OH treatment among adults with hypertension to improve the care of these patients and their complex blood pressure pathophysiology.

Orthostatic Hypotension Promotes the Progression From Mild Cognitive Impairment to Dementia in Type 2 Diabetes Mellitus.

CONTEXT: In type 2 diabetes mellitus (T2DM), orthostatic hypotension (OH) is associated with cognition, but the mechanisms governing the link between OH and cognition are still unclear. OBJECTIVE: We sought to analyze Alzheimer's disease (AD) biomarkers and the part of complement proteins in modulating the association of OH with cognitive impairment and examine whether OH could accelerate the clinical progression of mild cognitive impairment (MCI) to dementia in T2DM. METHODS: We recruited patients with T2DM with MCI and collected general healthy information and blood samples. Complement proteins of astrocyte-derived exosomes were isolated and AD biomarkers of neuronal cell-derived exosomes isolated were quantified by enzyme-linked immunosorbent assay. Cognitive assessments were performed at patient enrollment and follow-up. RESULTS: Mediation analysis showed that the influence of OH on cognition in T2DM was partly mediated by baseline AD biomarkers and complement proteins. Cox proportional-hazards regression proved the OH group had a higher risk of developing dementia compared to the T2DM without OH group. CONCLUSION: In T2DM with MCI patients, AD biomarkers and complement proteins mediate the effects of OH on cognitive impairment and OH may be a risk factor of progression from MCI to dementia in T2DM.

Study protocol for the Heads-Up trial: a phase II randomized controlled trial investigating head-up tilt sleeping to alleviate orthostatic intolerance in Parkinson's Disease and parkinsonism.

BACKGROUND: In persons with Parkinson's Disease (PD) or certain forms of atypical parkinsonism, orthostatic hypotension is common and disabling, yet often underrecognized and undertreated. About half of affected individuals also exhibit supine hypertension. This common co-occurrence of both orthostatic hypotension and supine hypertension complicates pharmacological treatments as the treatment of the one can aggravate the other. Whole-body head-up tilt sleeping (HUTS) is the only known intervention that may improve both. Evidence on its effectiveness and tolerability is, however, lacking, and little is known about the implementability. METHODS: In this double-blind multicenter randomized controlled trial (phase II) we will test the efficacy and tolerability of HUTS at different angles in 50 people with PD or parkinsonism who have both symptomatic orthostatic hypotension and supine hypertension. All participants start with one week of horizontal sleeping and subsequently sleep at three different angles, each maintained for two weeks. The exact intervention will vary between the randomly allocated groups. Specifically, the intervention group will consecutively sleep at 6°, 12° and 18°, while the delayed treatment group starts with a placebo angle (1°), followed by 6° and 12°. We will evaluate tolerability using questionnaires and compliance to the study protocol. The primary endpoint is the change in average overnight blood pressure measured by a 24-hour ambulatory blood pressure recording. Secondary outcomes include orthostatic blood pressure, orthostatic tolerance, supine blood pressure, nocturia and various other motor and non-motor tests and questionnaires. DISCUSSION: We hypothesize that HUTS can simultaneously alleviate orthostatic hypotension and supine hypertension, and that higher angles of HUTS are more effective but less tolerable. The Heads-Up trial will help to clarify the effectiveness, tolerability, and feasibility of this intervention at home and can guide at-home implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05551377; Date of registration: September 22, 2022.

A retrospective analysis of neurogenic orthostatic hypotension in long-term care facility residents with recurrent falls.

INTRODUCTION: Approximately 50 % of residents in long-term care facilities fall yearly and orthostatic hypotension accounts for a significant portion of them. Neurogenic orthostatic hypotension - a subtype of orthostatic hypotension - is important to be recognized as its management is far more complex; undertreatment of these older adults can lead to recurrent falls, high healthcare cost burden, and increased morbidity and mortality. The primary purpose of our study was to describe the rate of neurogenic orthostatic hypotension in older adults in a long-term care facility, with a secondary purpose to describe risk factors for neurogenic orthostatic hypotension in this population. METHODS: We conducted a retrospective case-control study of residents with recurrent falls at the Dayton Veteran's Affairs long-term care facility. Charts were manually reviewed. Inclusion criterion was three or more falls and age 65 or greater; we did not have exclusion criteria. ICD10 codes and most recent primary care physician notes were used to identify comorbidity diagnoses. Recent orthostatic vitals were used to assess orthostatic hypotension or neurogenic orthostatic hypotension diagnoses. RESULTS: Of our sample of 224 residents, we observed a prevalence of 20.5 % for neurogenic orthostatic hypotension and 32.1 % for orthostatic hypotension. Neither of them had diagnosis of neurogenic orthostatic hypotension documented. Parkinson's disease was associated with neurogenic orthostatic hypotension (OR-4.3; p = 0.002). Hypertension was prevalent in 69.6 % of residents with orthostatic vitals suggestive of neurogenic orthostatic hypotension. CONCLUSION: Older adults with recurrent falls at a long-term care facility meet criteria for neurogenic orthostatic hypotension diagnosis far more often than is documented. Common comorbidities associated with neurogenic orthostatic hypotension in this population include Parkinson's disease.

Neurogenic orthostatic hypotension in Parkinson's disease: is there a role for locus coeruleus magnetic resonance imaging?

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson's disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio-LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH-) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject's LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH- and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH- and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.

Orthostatic hypotension: Review and expert position statement.

Orthostatic hypotension is defined as a drop in systolic blood pressure of at least 20mmHg or a drop in diastolic blood pressure of at least 10mmHg within 3minutes of standing. It is a common disorder, especially in high-risk populations such as elderly subjects and patients with neurological diseases, and is associated with markedly increased morbidity and mortality. Its management can be challenging, particularly in cases where supine hypertension is associated with severe orthostatic hypotension. Education of the patient, non-pharmacological measures, and drug adaptation are the cornerstones of treatment. Pharmacological treatment should be individualized according to the severity, underlying cause, 24-hour blood pressure profile, and associated coexisting conditions. First-line therapies are midodrine and fludrocortisone, which may need to be combined for optimal care of severe cases.

Preoperative carbohydrate drink in fast-track primary total knee arthroplasty: a randomized controlled trial of 168 patients.

A key component in fast-track total knee arthroplasty (TKA) is early mobilization. Preoperative fasting might cause orthostatic hypotension and -intolerance which both can interfere with early mobilization. It was hypothesized that consuming a carbohydrate drink 2-3 hours prior to surgery is a viable option to reduce orthostatic hypotension, and as a result, improve rehabilitation. In this randomized controlled trial, all consecutive unilateral primary TKA patients were reviewed for eligibility. Exclusion criteria were American Society of Anesthesiologists (ASA) class above 3, older than 80 years of age, Diabetes Mellitus, and an insufficient comment of Dutch language. Patients were distributed in two groups. The control group was allowed to eat till 6 hours and drink clear fluids till 2 hours before surgery (standard treatment). The intervention group consumed, additionally to the standard treatment, a carbohydrate drink 2-3 hours before surgery. Blood pressure was measured both lying and standing as a measure for orthostatic hypotension during first time postoperative mobilization on day of surgery. A total of 168 patients were included. Prevalence of orthostatic hypotension in the control- and intervention group was 24 patients (34%) and 14 patients (19%) respectively, (p=0.05). Prevalence of orthostatic intolerance was 13 patients (19%) in the control group and 9 patients (13%) in the intervention group (p=0.32). No drink related adverse events occurred. In conclusion, taking a carbohydrate drink 2-3 hours before TKA significantly lowers the number of patients with orthostatic hypotension in early mobilization. However, the clinical relevance of the carbohydrate drink has to be studied further.

Advances in non-pharmacological management of Parkinson's disease complicated with blood pressure abnormalities.

Parkinson's disease (PD) often presents with autonomic dysregulation, leading to blood pressure irregularities such as neurogenic orthostatic hypotension (nOH), neurogenic supine hypertension (nSH), and postprandial hypotension (PPH). Unfortunately, these conditions remain prevalent and receive insufficient attention in scientific discourse. They not only cause complications like syncope, falls, and fractures but also result in long-term damage to vital organs, diminishing patients' quality of life. Early implementation of appropriate non-pharmacologic management is crucial to prevent severe adverse events later on. This review focuses on the types, clinical characteristics, mechanisms, and common non-pharmacologic management measures for PD complicated by abnormal blood pressure. By promoting early diagnosis, recognizing symptoms of abnormal blood pressure, and employing non-pharmacologic interventions such as health education, dietary adjustments, exercise, and Chinese medicine techniques, we aim to improve patients' symptoms and quality of life while providing practical guidance for managing PD-related blood pressure abnormalities.

Acute effect of levodopa on orthostatic hypotension and its association with motor responsiveness in Parkinson's disease: Results of acute levodopa challenge test.

OBJECTIVE: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change. METHODS: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology). RESULTS: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017). CONCLUSIONS: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both.

Orthostatic hypotension as an unusual presentation of spinal calcium pyrophosphate deposition disease: case report and review of literature.

Calcium pyrophosphate crystal deposition disease (CPPD), also known as pseudogout, with spinal involvement, is associated with clinical manifestations of acute nerve compression or chronic spinal stenosis. Precipitation of crystals of calcium pyrophosphate dihydrate in connective tissues can lead to acute inflammatory arthritis, degenerative chronic arthropathies, and radiographic evidence of cartilage calcification. We present a case of an 87-year-old woman, with unstudied chronic polyarthralgia and symptomatic orthostatic hypotension. It were documented acute calcium pyrophosphate deposition wrist arthritis, and cervical CT and MRI was suggestive of spinal involvement of CPPD. Workup excluded other causes of OH. Surgical approach could be indicated to minimize the symptoms, but it was contra-indicated due to the patient's performance status, so histological diagnosis was not possible. Muscle atrophy played an important part in the rapid progression of this insidious chronic disease. Conservative and symptomatic treatment achieve scarce short-term clinical improvement. Spinal involvement of CPPD was thought to be rare but recent studies show a higher prevalence than expected. We call for attention to the extent of structural changes that may occur when not early diagnosed nor treated. High clinical suspicion is required and this is, to our knowledge, the first report of orthostatic hypotension as a presentation of CPPD.

Droxidopa (Northera®) en hipotensión ortostática neurogénica por enfermedad de Parkinson / Droxidopa (Northera®) in orthostatic hypotension neurogenic due to Parkinson's disease

INTRODUCCIÓN: La hipotensión ortostática (HO) es definida como una reducción de la presión arterial sistólica de al menos 20 mmHg o una reducción de la presión arterial diastólica de al menos 10 mmHg, generalmente dentro de los primeros tres minutos después de estar de pie o de inclinar la cabeza hacia arriba sobre una mesa inclinada.1 Muchos trastornos pueden causar HO, siendo los principales mecanismos la disfunción barorrefleja, la depleción grave de volumen y los eventos adversos de los medicamentos. La HO se define como sintomática cuando la persona experimenta mareos, aturdimiento, síncope, dolor muscular en el cuello y los hombros e incluso angina al pararse.2. La OH neurogénica ocurre por disfunción barorrefleja y las neuronas simpáticas posganglionares no liberan noradrenalina de forma adecuada. La presión arterial cae progresivamente después de estar de pie porque la acumulación gravitacional de sangre en las piernas no puede compensarse mediante vasoconstricción simpática. La liberación subnormal de norepinefrina produce vasoconstricción alterada y volumen vascular intratorácico reducido, los cuales contribuyen a la hipotensión ortostática. La disfunción autonómica, incluida la disfunción barorrefleja que causa HO neurogénica, es una característica clínica común de las sinucleinopatías, que se caracterizan patológicamente por inclusiones neuronales citoplasmáticas (cuerpos de Lewy) o gliales que contienen alfasinucleína que se encuentran en el cerebro y los nervios autónomos periféricos de las personas con enfermedad de Parkinson. La prevalencia de HO neurogénica aumenta con la edad y la duración de la enfermedad, estando presente entre el 20 y el 60 % de las personas con esta enfermedad. TECNOLOGÍA: La droxidopa, un análogo de aminoácido sintético que se metaboliza a norepinefrina y puede aumentar la presión arterial al causar vasoconstricción de las arterias y venas periféricas. Se han observado aumentos menores y temporales en los niveles plasmáticos de norepinefrina después de la administración de droxidopa. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo del uso de droxidopa (Northera®) en hipotensión ortostática neurogénica por enfermedad de Parkinson. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. EVIDENCIA CLÍNICA: Hauser y cols. publicaron en 2028 un análisis integrado de los estudios disponibles sobre droxidopa frente a placebo para el tratamiento de la HO neurogénica en adultos con enfermedad de Parkinson. 7 El análisis incluyó tres ensayos clínicos de fase III multicéntricos (NOH301, NOH302 y NOH306B) que evaluaron droxidopa en personas con HO neurogénica sintomática por enfermedad de Parkinson y otras causas. 8­10 Estos ensayos inicialmente aleatorizaron un total de 332 personas con enfermedad de Parkinson (droxidopa [n=171] o placebo [n=162]), sin embargo, 25 personas (n=21 para droxidopa y n=5 para placebo) interrumpieron el tratamiento antes de las primeras mediciones de resultados y no se incluyeron en los análisis de eficacia. RECOMENDACIONES: No se hallaron recomendaciones para Argentina o Latinoamérica sobre la tecnología en la indicación evaluada. La Sociedad Internacional de Parkinson y Trastornos del Movimiento en 2019 menciona, entre otros medicamentos, que la droxidopa es posiblemente una opción de tratamiento para la HO neurogénica. 15 Las fundaciones de Parkinson para Estados Unidos y Canadá no la mencionan. El medicamento no ha sido evaluado, y por lo tanto no es cubierto, por la Agencia Canadiense de Medicamentos y Tecnologías en Salud (CADTH, su sigla del inglés Canadian Agency for Drugs and Technologies in Health) y el Plan de Beneficios Farmacéuticos (PBS, su sigla del inglés Pharmaceutical Benefits Scheme) de Australia. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización por parte de los Estados Unidos de droxidopa (Northera®) en adultos con hipotensión ortostática neurogénica sintomática se basa en tres ensayos clínicos aleatorizados de fase III. Cabe señalar que la agencia estadounidense la ha autorizado en 2014, mientras que la Agencia Europea de Medicamentos aún no lo ha hecho. Estos estudios demostraron que en pocas personas con hipotensión ortostática moderada por enfermedad de Parkinson, la droxidopa frente a placebo podría mejorar al muy corto plazo algunas puntuaciones para la evaluación de los síntomas, y aumentar la presión arterial sistólica y diastólica. Sin embargo, existen dudas si estas mejoras son clínicamente importantes y las personas que recibieron el fármaco presentaron mayores tasas de eventos adversos que llevaron a su discontinuación. No se halló evidencia que evalúe la droxidopa frente a otros tratamientos farmacológicos disponibles para la población objetivo, como tampoco si estos beneficios se mantienen en el tiempo. No se hallaron evaluaciones económicas ni recomendaciones para Argentina y Latinoamérica. Instituciones de referencia relevadas en países de altos ingresos no la mencionan dentro de sus recomendaciones y tampoco dan cobertura. Según los precio de adquisición relevados para Estados Unidos, el costo mensual del tratamiento sería aproximadamente de ARS 655.707 a 3.920.353.

Association of Supine Hypertension Versus Standing Hypotension With Adverse Events Among Middle-Aged Adults.

BACKGROUND: Management of orthostatic hypotension (OH) prioritizes prevention of standing hypotension, sometimes at the expense of supine hypertension. It is unclear whether supine hypertension is associated with adverse outcomes relative to standing hypotension. OBJECTIVES: To compare the long-term clinical consequences of supine hypertension and standing hypotension among middle-aged adults with and without OH. METHODS: The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure (BP) in adults aged 45 to 64 years, without neurogenic OH, between 1987 and 1989. We defined OH as a positional drop in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg, supine hypertension as supine BP≥140/≥90 mm Hg, and standing hypotension as standing BP≤105/≤65 mm Hg. Participants were followed for >30 years. We used Cox regression models to examine associations with cardiovascular disease events, all-cause mortality, falls, and syncope. RESULTS: Of 12 489 participants (55% female, 26% Black, mean age 54 years, SD 6), 4.4% had OH. Among those without OH (N=11 943), 19% had supine hypertension and 21% had standing hypotension, while among those with OH (N=546), 58% had supine hypertension and 38% had standing hypotension. Associations with outcomes did not differ by OH status (P-interactions >0.25). Supine hypertension was associated with heart failure (hazard ratio, 1.83 [95% CI, 1.68-1.99]), falls (hazard ratio, 1.12 [95% CI, 1.02-1.22]), and all-cause mortality (hazard ratio, 1.45 [95% CI, 1.37-1.54]), while standing hypotension was only significantly associated with mortality (hazard ratio, 1.06 [95% CI, 1.00-1.14]). CONCLUSIONS: Supine hypertension was associated with higher risk of adverse events than standing hypotension, regardless of OH status. This challenges conventional OH management, which prioritizes standing hypotension over supine hypertension.