Treatment of Supine Hypertension in Autonomic Failure

NCT00223717 | Completed Phase 1

• 1 other identifier: 010189
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension

Keywords

Supine Hypertension; Hypertension; Treatment; Autonomic failure; Pure autonomic failure; Multiple System Atrophy; Shy-Drager Syndrome

Outcome Measures

Primary Outcomes (1)

• Decrease in supine systolic blood pressure

  12 hours

Secondary Outcomes (1)

• Decrease in pressure natriuresis

  12 hours

Study Arms (2)

1: Active drug or intervention

EXPERIMENTAL

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; Drug: Nitroglycerin transdermal; Drug: Dipyridamole/ Aspirin (Aggrenox); Drug: Desmopressin (DDAVP); Drug: Sildenafil; Drug: Nifedipine; Drug: Hydralazine; Drug: Hydrochlorothiazide; 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

2: Placebo

PLACEBO COMPARATOR

placebo pill or patch

Drug: Placebo

Interventions

Clonidine DRUG

0.1-0.2mg po. Single dose.

Also known as: Catapres

1: Active drug or intervention

Nitroglycerin transdermal DRUG

0.05-0.2 mg patch. 1 application. Alone or in combination with DDAVP.

Also known as: Nitro-Dur

1: Active drug or intervention

Dipyridamole/ Aspirin (Aggrenox) DRUG

dipyridamole 200 mg and aspirin 25 mg po. Single dose.

Also known as: Aggrenox

1: Active drug or intervention

Desmopressin (DDAVP) DRUG

0.2 - 0.6mg po. Single dose. Alone or in combination with nitroglycerin transdermal or nifedipine

Also known as: DDAVP

1: Active drug or intervention

Sildenafil DRUG

25- 100 mg po. Single dose.

Also known as: Viagra

1: Active drug or intervention

Nifedipine DRUG

10-30 mg po. Single dose.

Also known as: Adalat

1: Active drug or intervention

Hydralazine DRUG

10-50 mg po. Single dose

1: Active drug or intervention

Hydrochlorothiazide DRUG

12.5-100 mg po. Single dose.

Also known as: Microzide

1: Active drug or intervention

Placebo DRUG

Po or patch. Single dose.

2: Placebo

Bosentan DRUG

62.5 -125 mg po. Single dose.

Also known as: Tracleer

1: Active drug or intervention

Diltiazem DRUG

30-60 mg po. Single dose.

Also known as: Cardizem

1: Active drug or intervention

Eplerenone DRUG

50-100 mg po. Single dose.

Also known as: Inspra

1: Active drug or intervention

guanfacine DRUG

1-3 mg po. Single dose.

Also known as: Tenex

1: Active drug or intervention

L-arginine DIETARY_SUPPLEMENT

6-17 g po. Single dose

1: Active drug or intervention

captopril DRUG

25-50 mg PO. Single dose.

Also known as: capoten

1: Active drug or intervention

carbidopa DRUG

25-200 mg PO. Single dose.

Also known as: Lodosyn

1: Active drug or intervention

losartan DRUG

25-200 mg PO. Single dose.

Also known as: cozaar

1: Active drug or intervention

metoprolol tartrate DRUG

25-100 mg PO. Single dose.

Also known as: lopressor

1: Active drug or intervention

nebivolol hydrochloride DRUG

2.5-40 mg PO. Single dose.

Also known as: Bystolic

1: Active drug or intervention

prazosin hydrochloride DRUG

0.5-1 mg PO. Single dose.

Also known as: Minipress

1: Active drug or intervention

tamsulosin hydrochloride DRUG

0.4-0.8 mg PO. Single dose.

Also known as: Flomax

1: Active drug or intervention

Head-up tilt. OTHER

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)

Also known as: HUT

1: Active drug or intervention

aliskiren DRUG

aliskiren (Tekturna) 150-300mg po single dose

Also known as: Tekturna

1: Active drug or intervention

Local heat stress OTHER

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

Also known as: heating pad

1: Active drug or intervention

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (15)

• Shibao C, Okamoto L, Biaggioni I. Pharmacotherapy of autonomic failure. Pharmacol Ther. 2012 Jun;134(3):279-86. doi: 10.1016/j.pharmthera.2011.05.009. Epub 2011 Jun 12.

  PMID: 21664375 BACKGROUND

• 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. doi: 10.1007/s11936-006-0002-1.

  PMID: 16533484 RESULT

• 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. doi: 10.1161/01.HYP.0000199982.71858.11. Epub 2006 Jan 3.

  PMID: 16391172 RESULT

• 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. doi: 10.1161/01.HYP.0000158835.94916.0c. Epub 2005 Feb 28.

  PMID: 15738343 RESULT

• 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. doi: 10.1097/00004872-200309000-00017.

  PMID: 12923400 RESULT

• Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin. 2002 May;20(2):291-301, vii. doi: 10.1016/s0733-8651(01)00005-4.

  PMID: 12119802 RESULT

• 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. doi: 10.1111/j.1524-6175.2001.00516.x.

  PMID: 11927799 RESULT

• 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. doi: 10.1161/01.cir.101.23.2710.

  PMID: 10851208 RESULT

• 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. doi: 10.1681/ASN.V10135.

  PMID: 9890307 RESULT

• 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. doi: 10.1161/01.hyp.30.5.1062.

  PMID: 9369256 RESULT

• 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. doi: 10.1161/HYPERTENSIONAHA.108.124552. Epub 2008 Dec 1.

  PMID: 19047577 RESULT

• 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. doi: 10.1161/HYPERTENSIONAHA.107.105171. Epub 2008 Apr 21.

  PMID: 18426998 RESULT

• Arnold AC, Okamoto LE, Gamboa A, Shibao C, Raj SR, Robertson D, Biaggioni I. Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure. Hypertension. 2013 Mar;61(3):701-6. doi: 10.1161/HYPERTENSIONAHA.111.00377. Epub 2012 Dec 24.

  PMID: 23266540 RESULT

• Arnold AC, Biaggioni I. Management approaches to hypertension in autonomic failure. Curr Opin Nephrol Hypertens. 2012 Sep;21(5):481-5. doi: 10.1097/MNH.0b013e328356c52f.

  PMID: 22801444 RESULT

• Garland EM, Gamboa A, Okamoto L, Raj SR, Black BK, Davis TL, Biaggioni I, Robertson D. Renal impairment of pure autonomic failure. Hypertension. 2009 Nov;54(5):1057-61. doi: 10.1161/HYPERTENSIONAHA.109.136853. Epub 2009 Sep 8.

  PMID: 19738158 RESULT

MeSH Terms

Conditions

Hypertension; Pure Autonomic Failure; Multiple System Atrophy; Shy-Drager Syndrome

Interventions

Clonidine; Nitroglycerin; Dipyridamole; Aspirin; Aspirin, Dipyridamole Drug Combination; Deamino Arginine Vasopressin; Sildenafil Citrate; Nifedipine; Hydralazine; Hydrochlorothiazide; Bosentan; Diltiazem; Eplerenone; Guanfacine; Arginine; Captopril; Carbidopa; Losartan; Metoprolol; Nebivolol; Prazosin; Tamsulosin; aliskiren

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Hypotension

Intervention Hierarchy (Ancestors)

Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitro Compounds; Organic Chemicals; Pyrimidines; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Drug Combinations; Pharmaceutical Preparations; Arginine Vasopressin; Vasopressins; Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Piperazines; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Dihydropyridines; Pyridines; Phthalazines; Pyridazines; Chlorothiazide; Benzothiadiazines; Thiazides; Benzenesulfonamides; Benzazepines; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Guanidines; Amidines; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Amino Acids, Basic; Amino Acids; Amino Acids, Diamino; Amino Acids, Essential; Proline; Imino Acids; Amino Acids, Cyclic; Methyldopa; Dihydroxyphenylalanine; Catecholamines; Amines; Hydrazines; Catechols; Biphenyl Compounds; Tetrazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Ethanolamines; Benzopyrans; Pyrans; Quinazolines

Study Officials

• Italo Biaggioni, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: September 14, 2005
• First Posted: September 22, 2005
• Study Start: January 1, 2001
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: October 13, 2017

Record last verified: 2017-10

Locations

US (1)