Official Title: “Treatment of Supine Hypertension in Patients With Autonomic Failure”

Supine hypertension is a common problem that affects at least 50% of patients with primary autonomic failure. Supine hypertension can be severe, and complicates the treatment of orthostatic hypotension. Drugs used for the treatment of orthostatic hypotension (eg, fludrocortisone and pressor agents), worsen supine hypertension. High blood pressure may also cause target organ damage in this group of patients. The pathophysiologic mechanisms causing supine hypertension in patients with autonomic failure have not been defined.

In a study, we, the investigators at Vanderbilt University, examined 64 patients with AF, 29 with pure autonomic failure (PAF) and 35 with multiple system atrophy (MSA). 66% of patients had supine systolic (systolic blood pressure [SBP] > 150 mmHg) or diastolic (diastolic blood pressure [DBP] > 90 mmHg) hypertension (average blood pressure [BP]: 179 ± 5/89 ± 3 mmHg in 21 PAF and 175 ± 5/92 ± 3 mmHg in 21 MSA patients). Plasma norepinephrine (92 - 15 pg/mL) and plasma renin activity (0.3 ± 0.05 ng/mL per hour) were very low in a subset of patients with AF and supine hypertension. (Shannon et al., 1997).

Our group has showed that a residual sympathetic function contributes to supine hypertension in patients with severe autonomic failure and that this effect is more prominent in patients with MSA than in those with PAF (Shannon et al., 2000). MSA patients had a marked depressor response to low infusion rates of trimethaphan, a ganglionic blocker; the response in PAF patients was more variable. At 1 mg/min, trimethaphan decreased supine SBP by 67 +/- 8 and 12 +/- 6 mmHg in MSA and PAF patients, respectively (P < 0.0001). MSA patients with supine hypertension also had greater SBP response to oral yohimbine, a central alpha2 receptor blocker, than PAF patients. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. This result suggests that residual sympathetic activity drives supine hypertension in MSA; in contrast, supine hypertension in PAF.

It is hoped that from this study will emerge a complete picture of the supine hypertension of autonomic failure. Understanding the mechanism of this paradoxical hypertension in the setting of profound loss of sympathetic function will improve our approach to the treatment of hypertension in autonomic failure, and it could also contribute to our understanding of hypertension in general.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: April 2010

Overnight Medication Trials:

Patients will be studied on the GCRC while in 150 mEq/day sodium balance and on a diet free of substances which interfere with catecholamine determination. Subjects will be asked to use the bathroom to empty their bladder at 8:00 PM. They will be given a randomly chosen medication bosentan (Tracleer) 62.5 -125 mg po, captopril 25-50mg po, carbidopa 25-200mg po, clonidine 0.1-0.2mg po, desmopressin 0.2 - 0.6mg po (DDAVP), ¬diltiazem 30-60 mg po, dipyridamole 200 mg and aspirin 25 mg po (Aggrenox), eplerenone (Inspra) 50-100 mg po, guanfacine (Tenex) 1-3 mg po, hydralazine 10-50 mg po, hydrochlorothiazide 12.5-100 mg po, L- arginine 6-17 g po, losartan 25-100mg po, metoprolol tartrate (Lopressor) 25-100 mg po, nebivolol hydrochloride (Bystolic) 2.5-40 mg po, nitroglycerin-transdermal 0.05-0.2 mg patch, nifedipine (adalat) doses 10-30 mg, prazosin hydrochloride 0.5-1 mg po, sildenafil (Viagra) 25- 100 mg po, tamsulosin hydrochloride (Flomax) 0.4-0.8 mg po. The combination desmopressin 0.2 mg po (DDAVP) and nitroglycerin-transdermal 0.05-0.2 mg. The combinations desmopressin 0.2 mg po and nifedipine (10-30 mg). A placebo pill or skin patch will be done as a control to measure their supine blood pressure without medication intervention. They will then be asked to lie down with the head of the bed elevated 10 degrees. An automated blood pressure cuff (Dinamap) will be wrapped around an upper arm and blood pressure will be measured automatically 2 times in a row every 2 hours. At 8 AM the following morning the study ends.

The subjects will then stand at the bedside as motionless as possible for 30 minutes for blood pressure and heart rate determination.

Urine will be collected for 24 hours for determination of volume and sodium, potassium and catecholamines (for some medication trials) in 12 hour segments, from 8 a.m. to 8 p.m. and 8 p.m. to 8 a.m. to ascertain how the medications affect urine production.

For medication trials affecting renal Na and/or water regulation (e.g. desmopressin, carbidopa), blood samples will be collected (5 mL, 1 teaspoon) at 8 PM and 8 AM for determination of a basic metabolic panel.

Raising the head of the bed during the night is a non-pharmacologic measure that may reduce supine blood pressure, nocturnal natriuresis and improve orthostatic hypotension the following morning in autonomic failure patients with supine hypertension. However, it is not known if tilting the bed with the head up is better than raising only the head of the bed. To compare the effect of these two ways of raising the head of the bed on nighttime blood pressure and nocturnal natriuresis, some patients will undergo two additional tests. On two separate nights (either consecutive or not), patients will receive the placebo and will be assigned by simple randomization to lie down in one of two different bed positions:

1. The head of the bed elevated 10 degrees (~ 7 inches); or

2. The whole bed tilted head-up 5 degrees in reverse trendelenburg (head of the bed elevated ~7 inches).

Blood pressure, orthostatic tolerance at 8 AM and urine collections will be performed as described above.

Intervention(s) in this Clinical Trial

• Drug: Clonidine
  • 0.1-0.2mg po. Single dose.
• Drug: Nitroglycerin transdermal
  • 0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP.
• Drug: Dipyridamole/ Aspirin (Aggrenox)
  • dipyridamole 200 mg and aspirin 25 mg po. Single dose.
• Drug: Desmopressin (DDAVP)
  • 0.2 - 0.6mg po. Single dose. Alone or in combination with nitroglycerin transdermal or nifedipine
• Drug: Sildenafil
  • 25- 100 mg po. Single dose.
• Drug: Nifedipine
  • 10-30 mg po. Single dose.
• Drug: Hydralazine
  • 10-50 mg po. Single dose
• Drug: Hydrochlorothiazide
  • 12.5-100 mg po. Single dose.
• Drug: Placebo
  • Po or patch. Single dose.
• Drug: Bosentan
  • 62.5 -125 mg po. Single dose.
• Drug: Diltiazem
  • 30-60 mg po. Single dose.
• Drug: Eplerenone
  • 50-100 mg po. Single dose.
• Drug: guanfacine
  • 1-3 mg po. Single dose.
• Dietary Supplement: L-arginine
  • 6-17 g po. Single dose
• Drug: captopril
  • 25-50 mg PO. Single dose.
• Drug: carbidopa
  • 25-200 mg PO. Single dose.
• Drug: losartan
  • 25-200 mg PO. Single dose.
• Drug: metoprolol tartrate
  • 25-100 mg PO. Single dose.
• Drug: nebivolol hydrochloride
  • 2.5-40 mg PO. Single dose.
• Drug: prazosin hydrochloride
  • 0.5-1 mg PO. Single dose.
• Drug: tamsulosin hydrochloride
  • 0.4-0.8 mg PO. Single dose.
• Other: Head-up tilt.
  • Head of the bed elevated 10 degrees (7 inch) or whole bed tilted head-up 5 degrees in reverse trendelenburg (head of the bed elevated 7 inches)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Decrease in supine systolic blood pressure
  • Time Frame: 12 hours
    Safety Issue?: No

Secondary Measures

• Decrease in pressure natriuresis
  • Time Frame: 12 hours
    Safety Issue?: No

Inclusion Criteria:

• Patients with autonomic failure and with supine hypertension from all races

Exclusion Criteria:

• All medical students
• Pregnant women
• High-risk patients (e.g. heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction)
• History of serious allergies or asthma.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Italo Biaggioni, MD Principal Investigator Vanderbilt University  

Overall Contact: Bonnie Black, RN  adcresearch@vanderbilt.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00223717

Study ID Number: 010189

ClinicalTrials.gov Identifier: NCT00223717

Health Authority: United States: Food and Drug Administration

Autonomic Dysfunction Center Website