By Harini Sarva, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York Presbyterian Hospital

Dr. Sarva reports no financial relationships relevant to this field of study.

SYNOPSIS: This double-center, double-blind, randomized, controlled trial compared the efficacy of pyridostigmine bromide vs. fludrocortisone and demonstrated that pyridostigmine bromide was not as effective as fludrocortisone. The authors also provided evidence for the efficacy of fludrocortisone in treating neurogenic orthostatic hypotension.

SOURCE: Schreglmann SR, Buchele F, Sommerauer M, et al. Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson’s disease. Eur J Neurol 2017;24:545-551.

This double-center, double-blind, randomized, controlled trial compared the efficacy of pyridostigmine bromide (PB) with fludrocortisone for orthostatic hypotension (OH) in Parkinson’s disease (PD). It was a Phase II, non-inferiority trial that included patients aged 50-80 years with a diagnosis of PD according to the U.K. Brain Bank Criteria and symptomatic OH (systolic blood pressure [SBP] drop by 20 mmHg or diastolic blood pressure [DBP] drop by 10 mmHg within three minutes of standing). Patients on medications that regulate blood pressure, with systemic diseases such as diabetes mellitus, or with clinical features of cerebellar involvement or multiple system atrophy (MSA) were excluded. The two trial arms were of 14 days duration and the subsequent washout was 21 days prior to crossover. Visits were conducted immediately before drug initiation and immediately after the final dose. The following were performed on the subjects: UPDRS Part III for motor assessment, Montreal Cognitive Assessment, Hospital Anxiety and Depression Scale, Zurich autonomic questionnaire, Orthostatic Hypotension Severity Assessment, non-invasive central blood pressure measures using pulse wave analysis by applanation tonometry, and cardiovascular monitoring using the Schellong maneuver. Home blood pressure in the sitting position consisted of automated repeat morning and evening measurements for seven days. PB was started at 90 mg per day for three days before increasing to 180 mg per day. Fludrocortisone was started at 0.1 mg per day before increasing to 0.2 mg per day after three days. Drug calendars and collection of empty medication boxes were used to assess drug compliance. Thirteen patients were recruited and four dropped out. After an interim analysis showed futility of PB in comparison to fludrocortisone, researchers ended the study and performed an intent-to-treat analysis. Fludrocortisone improved the primary outcome measure of improvement in DBP drop by 37% as assessed by Schellong maneuver and mean arterial blood pressure standing by 15%, whereas PB had no significant effect. Peripheral SBP supine and SBP home measurements improved by 11% with fludrocortisone, but there was no effect with PB. However, subjective symptom severity did not correlate with the numerical improvements. Although PB lowered central mean supine blood pressure, it remained unchanged with fludrocortisone. Neither demonstrated any significant improvement on motor, cognitive, or psychiatric assessments. Transient adverse events were mild for each drug and did not cause study dropout.

COMMENTARY

Orthostatic hypotension remains a major quality-of-life issue for patients with PD. Although clinicians try conservative measures prior to starting medications such as fludrocortisone, midodrine, and now droxidopa, consensus on which medication to choose and dosing still remains an issue. Much of the evidence for using these medications comes from relatively small studies with subjects exhibiting various causes of neurogenic orthostatic hypotension, such as MSA and pure autonomic failure. Difficulty in recruitment, along with various means of measuring blood pressure changes, remain major challenges to defining precise algorithms. In addition, the pathological mechanisms of developing OH in the various conditions is different. In MSA, the lesion site is central and preganglionic, whereas in PD it is peripheral and postganglionic, further adding to the complexity of OH and developing consensus management strategies. In addition, difficulty in accurately measuring central blood pressure changes and their role in accurately predicting vascular response to treatments of orthostatic hypotension have not been well-studied in PD. This study is important in that it shows that fludrocortisone is effective in treating OH in PD, albeit in a small sample size, and that it may not increase central blood pressure, suggesting that it is a relatively safe treatment. However, the small sample size and the relatively large dropout rate are major limitations of this study. Further evidence is required to first set up a consensus for accurate BP measurements in PD patients and then to provide an appropriate treatment algorithm. For now, it is still important to exhaust conservative measures, such as increasing salt and fluid intake, using compression stockings, reducing antihypertensives, and possibly adjusting the dose of dopaminergic medications, before initiating blood pressure-raising medications. Anecdotally, we know that improving OH can improve motor and cognitive symptoms, and further research in this area also is needed to determine when blood pressure support should be initiated to improve quality of life and functionality.