Combined Renin Inhibition/Beta-blockade

• Sponsor: The Rogosin Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00627861
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Duration (Months): 17.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Antihypertensive drug treatment is effective in only about 50% of patients. One mechanism responsible for treatment failure is a drug related stimulation of the renin-angiotension-aldosterone-system (RAAS). Several classes of medications that treat hypertension by blocking the RAAS system have been developed. However, the kidney responds to these drug treatments by producing greater amounts of renin. This high level of renin can reduce the effectiveness of some of these medications, ultimately causing the blood pressure to rise. This is one reason why blood pressure can be difficult to control in a certain percentage of patients.

The hypothesis to be tested in the proposed study is that beta-adrenergic blockade (β-blockade), when superimposed upon aliskiren, a drug that competitively inhibits plasma renin activity (PRA) but stimulates the release of renin by the kidneys (plasma renin concentration [PRC]), can suppress the reactive increase in PRC that occurs during aliskiren monotherapy.

The primary aim of this study is to measure plasma renin concentration (PRC) and plasma renin activity (PRA) levels during renin inhibition with aliskiren and combined renin inhibition/β-blocker treatment to determine whether the addition of a β-blocker attenuates the rise in plasma renin concentration (PRC). A secondary aim is to determine whether combined treatment further suppresses PRA and blood pressure.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Aliskiren; Drug: Extended-release metoprolol	N/A

Detailed Description

The renin-angiotensin-aldosterone system (RAAS) plays a central role in the maintenance of normal blood pressure (BP) homeostasis. Derangements in the regulation of this system, predominantly due to the failure to appropriately suppress renin secretion by the kidney, contribute to the pathogenesis of hypertension and its cardiovascular, renal and cerebrovascular complications.

Several classes of antihypertensive medications that interrupt the RAAS have been developed. These include agents that block angiotensin II (Ang II) binding to the AT1 receptor (Ang II receptor blockers [ARB]), inhibit conversion of Ang I to Ang II (angiotensin converting enzyme [ACE] inhibitors), and suppress renal secretion of renin (beta-adrenergic receptor blocker). These agents effectively lower BP, particularly in the hypertensive patient with an unsuppressed plasma renin activity (PRA) level, and significantly improve survival in cardiovascular diseases in which PRA levels are often elevated (e.g., heart failure, myocardial infarction).

Renin secretion is regulated, in part, by feedback inhibition due to Ang II binding to the juxtaglomerular cell (JG). Interruption of Ang II generation or its receptor binding during treatment with an ACE inhibitor or ARB, respectively, stimulates renin secretion because feedback inhibition is attenuated and renal perfusion pressure is reduced. The consequent, reactive rise in PRA that occurs during treatment with these drugs can limit their antihypertensive efficacy because Ang I and subsequently, Ang II levels increase.

These observations reinforce the theoretical and practical importance of pharmacologic suppression of renin secretion to prevent the reactive rise in PRA that occurs during treatment with ACE inhibitors and ARBs. β-blockers suppress renin secretion by inhibiting β1-adrenergic receptors located on JG cells. PRA and Ang II levels are highly correlated and these decrease commensurately during treatment with a β-blocker.

Aliskiren is an orally active, non-peptide renin inhibitor. Its antihypertensive efficacy is due to the competitive antagonism of the renin-mediated conversion of angiotensinogen to Ang

1. During aliskiren treatment, PRA and Ang II levels decrease significantly. Unlike β-blockade, in which the PRA level decreases as a consequence of reduced renal secretion of renin, aliskiren treatment decreases PRA in response to the direct, competitive inhibition of renin. Although PRA decreases, the aliskiren-mediated decrease in plasma Ang II level stimulates renal renin secretion. Therefore, although aliskiren and β-blockers both decrease

PRA levels, they have divergent effects on the plasma concentration of renin (PRC):

β-blockers decrease it and aliskiren increases it. The reactive rise in PRC has potential implications regarding the antihypertensive efficacy of aliskiren - high PRC levels theoretically can overcome the competitive inhibition of renin by aliskiren, thereby increasing PRA, Ang II, and BP.

Aliskiren has been studied as monotherapy and in combination with other antihypertensive drugs, including hydrochlorothiazide, valsartan, and amlodipine. It has not been studied in the presence of a β-blocker. Proposals for future studies include pursuing whether or not there are hypertensives who are resistant to aliskiren, what the mechanism(s) is for the resistance and ways to overcome the resistance.

This is a prospective, open-label study of the effect of the sequential addition of a β-blocker (extended release metoprolol) to aliskiren on the levels of plasma renin activity and plasma renin concentration in subjects with uncomplicated hypertension.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Renin System Responses to Combined Renin Inhibition and Beta Adrenergic Blockade
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Aliskiren and metoprolol succinate

Drug: Aliskiren; 150mg orally daily for 6 weeks. Dose may increase to 300mg orally daily dependent upon blood pressure parameters set by the protocol.; Other Names: Tekturna ; Drug: Extended-release metoprolol; 50mg orally daily for 1 week, dose will increase to 100mg orally daily or decrease to 25mg daily for a second week dependent upon blood pressure parameters set by the protocol. Subjects will take metoprolol for a total of 2 weeks, then be tapered off of it over 5-7 days.; Other Names: Toprol-XL

Outcome Measures

Primary Outcome Measures

1. Plasma Renin Concentration [5th, 6th, 7th, 9th, 10th, 11th, 12th weeks]

Secondary Outcome Measures

1. Plasma Renin Activity [screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks]

   The blood test, plasma renin activity or PRA, is being measured during the visits outlined.

2. Blood Pressure [all visits (weekly for 12 weeks)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Twenty subjects with a history of hypertension with the following inclusion criteria will be enrolled:

• Age 18-80 years

• Stage 1 (systolic 140-159 mm Hg or diastolic 90-99 mmHg) or Stage 2 (systolic >160 mm Hg or diastolic >100 mmHg) or current treatment with antihypertensive medication.

• PRA ≥0.65 ng/ml/h. If PRA is below this level during the screening period, due to treatment with a beta-blocker or central α2-receptor agonist, the subject may be enrolled and the PRA level re-checked after treatment is tapered off.

Exclusion Criteria:

• History of diabetes requiring pharmacologic treatment with an oral or parenteral hypoglycemic agent, including insulin

• TIA, stroke or myocardial infarction

• History of asthma or COPD

• Cockcroft Gault estimated GFR <60 ml/min/1.73 m2

• Previous adverse events during treatment with a β-blocker or aliskiren

• ALT level twice normal

• Secondary forms of hypertension (e.g., renovascular, primary aldosteronism)

• PRA<0.65 ng/ml/h after discontinuation of antihypertensive medication

• Systolic BP>180 mm Hg, diastolic BP>105 mm Hg

• Pregnant or breastfeeding, or planning pregnancy during the study period

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Rogosin Institute	New York	New York	United States	10021

Sponsors and Collaborators

• The Rogosin Institute

Investigators

• Principal Investigator: Jon D Blumenfeld, M.D., The Rogosin Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

• Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet. 2006 Oct 21;368(9545):1449-56. Review. Erratum in: Lancet. 2006 Dec 16;368(9553):2124.

• Responsible Party: The Rogosin Institute
• ClinicalTrials.gov Identifier: NCT00627861
• Other Study ID Numbers: 0712009564
• First Posted: Mar 4, 2008
• Last Update Posted: Nov 24, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Hypertension; Metoprolol

Study Results

Participant Flow

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for 2 additional weeks of treatment.
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for 2 additional weeks of treatment.
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Plasma Renin Concentration
Time Frame	5th, 6th, 7th, 9th, 10th, 11th, 12th weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for 2 additional weeks of treatment.
Measure Participants	1
Week 5	16.5
Week 6	13.5
Week 7	20.5
Week 9	22
Week 10	2.7
Week 11	4.4
Week 12	3.2

2. Secondary Outcome

Title	Plasma Renin Activity
Description	The blood test, plasma renin activity or PRA, is being measured during the visits outlined.
Time Frame	screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for an additional 2 weeks.
Measure Participants	1
Screening	2.07
Week 4	1.22
Week 6	0.28
Week 7	0.18
Week 9	0.28
Week 10	0.07
Week 11	0.03
Week 12	0.06

3. Secondary Outcome

Title	Blood Pressure
Time Frame	all visits (weekly for 12 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for an additional 2 weeks
Measure Participants	1
Week 1-Systolic	146
Week 1-Diastolic	64
Week 2-Systolic	144
Week 2-Diastolic	88
Week 3-Systolic	148
Week 3-Diastolic	90
Week 4-Systolic	148
Week 4-Diastolic	92
Week 5-Systolic	156
Week 5-Diastolic	92
Week 6-Systolic	150
Week 6-Diastolic	84
Week 7-Systolic	157
Week 7-Diastolic	89
Week 8-Systolic	147
Week 8-Diastolic	76
Week 9-Systolic	129
Week 9 -Diastolic	94
Week 10-Systolic	139
Week 10-Diastolic	79
Week 11-Systolic	170
Week 11-Diastolic	90
Week 12-Systolic	146
Week 12-Diastolic	78

Adverse Events

Arm/Group Title	Aliskiren and Metoprolol
Arm/Group Description	Aliskiren was administered for 4 weeks and then Metoprol was added for 2 additional weeks of treatment.
All Cause Mortality
	Aliskiren and Metoprolol
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Aliskiren and Metoprolol
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Aliskiren and Metoprolol
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Immune system disorders
Leukocytosis	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.