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Treatment of Supine Hypertension in Autonomic Failure

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ClinicalTrials.gov Identifier: NCT00223717
Recruitment Status : Completed
First Posted : September 22, 2005
Last Update Posted : October 13, 2017
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Hypertension Drug: Clonidine Drug: Nitroglycerin transdermal Drug: Dipyridamole/ Aspirin (Aggrenox) Drug: Desmopressin (DDAVP) Drug: Sildenafil Drug: Nifedipine Drug: Hydralazine Drug: Hydrochlorothiazide Drug: Placebo Drug: Bosentan Drug: Diltiazem Drug: Eplerenone Drug: guanfacine Dietary Supplement: L-arginine Drug: captopril Drug: carbidopa Drug: losartan Drug: metoprolol tartrate Drug: nebivolol hydrochloride Drug: prazosin hydrochloride Drug: tamsulosin hydrochloride Other: Head-up tilt. Drug: aliskiren Other: Local heat stress Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: The Pathophysiology and Treatment of Supine Hypertension in Patients With Autonomic Failure
Study Start Date : January 2001
Actual Primary Completion Date : January 2017
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1: Active drug or intervention
Clonidine, Nitroglycerin transdermal, Dipyridamole/ Aspirin (Aggrenox), Desmopressin (DDAVP), Sildenafil, Nifedipine, Hydralazine, Hydrochlorothiazide, Bosentan, Diltiazem, Eplerenone, guanfacine, L-arginine, captopril, carbidopa, losartan, metoprolol tartrate, nebivolol hydrochloride, prazosin hydrochloride, tamsulosin hydrochloride, Head-up tilt, aliskiren, local heat stress
Drug: Clonidine
0.1-0.2mg po. Single dose.
Other Name: Catapres

Drug: Nitroglycerin transdermal
0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP.
Other Name: Nitro-Dur

Drug: Dipyridamole/ Aspirin (Aggrenox)
dipyridamole 200 mg and aspirin 25 mg po. Single dose.
Other Name: Aggrenox

Drug: Desmopressin (DDAVP)
0.2 - 0.6mg po. Single dose. Alone or in combination with nitroglycerin transdermal or nifedipine
Other Name: DDAVP

Drug: Sildenafil
25- 100 mg po. Single dose.
Other Name: Viagra

Drug: Nifedipine
10-30 mg po. Single dose.
Other Name: Adalat

Drug: Hydralazine
10-50 mg po. Single dose

Drug: Hydrochlorothiazide
12.5-100 mg po. Single dose.
Other Name: Microzide

Drug: Bosentan
62.5 -125 mg po. Single dose.
Other Name: Tracleer

Drug: Diltiazem
30-60 mg po. Single dose.
Other Name: Cardizem

Drug: Eplerenone
50-100 mg po. Single dose.
Other Name: Inspra

Drug: guanfacine
1-3 mg po. Single dose.
Other Name: Tenex

Dietary Supplement: L-arginine
6-17 g po. Single dose

Drug: captopril
25-50 mg PO. Single dose.
Other Name: capoten

Drug: carbidopa
25-200 mg PO. Single dose.
Other Name: Lodosyn

Drug: losartan
25-200 mg PO. Single dose.
Other Name: cozaar

Drug: metoprolol tartrate
25-100 mg PO. Single dose.
Other Name: lopressor

Drug: nebivolol hydrochloride
2.5-40 mg PO. Single dose.
Other Name: Bystolic

Drug: prazosin hydrochloride
0.5-1 mg PO. Single dose.
Other Name: Minipress

Drug: tamsulosin hydrochloride
0.4-0.8 mg PO. Single dose.
Other Name: Flomax

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)
Other Name: HUT

Drug: aliskiren
aliskiren (Tekturna) 150-300mg po single dose
Other Name: Tekturna

Other: Local heat stress
Passive heat-stress using a commercial heating pad applied over the abdomen and part of the torso
Other Name: heating pad

Placebo Comparator: 2: Placebo
placebo pill or patch
Drug: Placebo
Po or patch. Single dose.




Primary Outcome Measures :
  1. Decrease in supine systolic blood pressure [ Time Frame: 12 hours ]

Secondary Outcome Measures :
  1. Decrease in pressure natriuresis [ Time Frame: 12 hours ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00223717


Locations
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Italo Biaggioni, MD Vanderbilt University

Additional Information:
Publications of Results:

Other Publications:
Responsible Party: Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00223717     History of Changes
Other Study ID Numbers: 010189
First Posted: September 22, 2005    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017

Keywords provided by Italo Biaggioni, Vanderbilt University:
Supine Hypertension
Hypertension
Treatment
Autonomic failure
Pure autonomic failure
Multiple System Atrophy
Shy-Drager Syndrome

Additional relevant MeSH terms:
Autonomic Nervous System Diseases
Nervous System Diseases
Sensory System Agents
Peripheral Nervous System Agents
Hypertension
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Primary Dysautonomias
Aspirin
Dipyridamole
Aspirin, Dipyridamole Drug Combination
Clonidine
Sildenafil Citrate
Carbidopa
Captopril
Metoprolol
Nifedipine
Nebivolol
Nitroglycerin
Diltiazem
Hydralazine
Tamsulosin
Losartan
Bosentan
Hydrochlorothiazide
Guanfacine
Prazosin
Eplerenone
Deamino Arginine Vasopressin