Treatment of Supine Hypertension in Autonomic Failure - Full Text View

Sponsor:	Vanderbilt University
Information provided by:	Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00223717

Purpose

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	Intervention	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.	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Efficacy Study
Official Title:	The Pathophysiology and Treatment of Supine Hypertension in Patients With Autonomic Failure

Resource links provided by NLM:

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Acetylsalicylic acid Verapamil Nitroglycerin Dipyridamole Hydrochlorothiazide Desmopressin Prazosin Prazosin hydrochloride Nifedipine Guanfacine Guanfacine hydrochloride Diltiazem hydrochloride Dexverapamil Carbidopa Diltiazem Metoprolol Metoprolol Tartrate Desmopressin acetate Captopril TX 3301 Arginine Hydralazine Metoprolol succinate Nebivolol Tamsulosin Tamsulosin hydrochloride Losartan Metoprolol fumarate Losartan potassium Sildenafil Diltiazem malate Bosentan Sildenafil citrate Verapamil hydrochloride Hydralazine hydrochloride Arginine hydrochloride Clonidine Clonidine hydrochloride

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:

Decrease in supine systolic blood pressure [ Time Frame: 12 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Decrease in pressure natriuresis [ Time Frame: 12 hours ] [ Designated as safety issue: No ]

Estimated Enrollment:	160
Study Start Date:	June 2001
Estimated Study Completion Date:	April 2010
Estimated Primary Completion Date:	April 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active drug or intervention: Experimental	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: 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)
2: Placebo: Placebo Comparator	Drug: Placebo Po or patch. Single dose.

Arms

Assigned Interventions

1: Active drug or intervention: Experimental

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: 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)

2: Placebo: Placebo Comparator

Drug: Placebo

Po or patch. Single dose.

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00223717

Contacts

Contact: Bonnie Black, RN

adcresearch@vanderbilt.edu

Locations

United States, Tennessee
Vanderbilt University	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Bonnie Black, RN adcresearch@vanderbilt.edu
Principal Investigator: Italo Biaggioni, MD
Sub-Investigator: David Robertson, MD
Sub-Investigator: Satish Raj, MD
Sub-Investigator: Alfredo Gamboa, MD
Sub-Investigator: Cyndya Shibao, MD
Sub-Investigator: Andre Diedrich, MD
Sub-Investigator: Luis E Okamoto, MD

Sponsors and Collaborators

Vanderbilt University

Investigators

Principal Investigator:

Italo Biaggioni, MD

Vanderbilt University

More Information

Additional Information:

Autonomic Dysfunction Center Website This link exits the ClinicalTrials.gov site

Publications:

Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic dysfunction. Curr Treat Options Cardiovasc Med. 2006 Apr;8(2):105-9.

Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, Robertson D, Biaggioni I. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. 2006 Mar;47(3):522-6. Epub 2006 Jan 3.

Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. 2005 Apr;45(4):469-76. Epub 2005 Feb 28.

Diedrich A, Jordan J, Tank J, Shannon JR, Robertson R, Luft FC, Robertson D, Biaggioni I. The sympathetic nervous system in hypertension: assessment by blood pressure variability and ganglionic blockade. J Hypertens. 2003 Sep;21(9):1677-86. Erratum in: J Hypertens. 2003 Nov;21(11):2204-5.

Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002 May;20(2):291-301, vii. Review.

Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens (Greenwich). 2002 Mar-Apr;4(2):139-45.

Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, Biaggioni I. Sympathetically mediated hypertension in autonomic failure. Circulation. 2000 Jun 13;101(23):2710-5.

Jordan J, Shannon JR, Pohar B, Paranjape SY, Robertson D, Robertson RM, Biaggioni I. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999 Jan;10(1):35-42.

Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997 Nov;30(5):1062-7.

Okamoto LE, Gamboa A, Shibao C, Black BK, Diedrich A, Raj SR, Robertson D, Biaggioni I. Nocturnal blood pressure dipping in the hypertension of autonomic failure. Hypertension. 2009 Feb;53(2):363-9. Epub 2008 Dec 1.

Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008 Jun;51(6):1531-6. Epub 2008 Apr 21.

Responsible Party:	Vanderbilt University ( Italo Biaggioni )
Study ID Numbers:	010189
Study First Received:	September 14, 2005
Last Updated:	August 14, 2009
ClinicalTrials.gov Identifier:	NCT00223717 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Vanderbilt University:

Supine Hypertension
Hypertension
Treatment
Autonomic failure

Pure autonomic failure
Multiple System Atrophy
Shy-Drager Syndrome

Additional relevant MeSH terms:

Neurotransmitter Agents
Coagulants
Adrenergic Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Hormone Antagonists
Diuretics
Hematologic Agents
Hydralazine
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Calcium Channel Blockers
Membrane Transport Modulators
Nitroglycerin
Guanfacine

Prazosin
Therapeutic Uses
Tamsulosin
Angiotensin-Converting Enzyme Inhibitors
Cardiovascular Diseases
Nervous System Diseases
Nebivolol
Adrenergic alpha-Antagonists
Antihypertensive Agents
Hydrochlorothiazide
Hemostatics
Protease Inhibitors
Eplerenone
Aldosterone Antagonists
Natriuretic Agents

ClinicalTrials.gov processed this record on November 27, 2009