Combined Renin Inhibition/Beta-blockade

October 26, 2015 updated by: The Rogosin Institute

Renin System Responses to Combined Renin Inhibition and Beta Adrenergic Blockade

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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 I. 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 Type

Interventional

Enrollment (Actual)

1

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10021
        • The Rogosin Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Plasma Renin Concentration
Time Frame: 5th, 6th, 7th, 9th, 10th, 11th, 12th weeks
5th, 6th, 7th, 9th, 10th, 11th, 12th weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma Renin Activity
Time Frame: screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks
The blood test, plasma renin activity or PRA, is being measured during the visits outlined.
screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks
Blood Pressure
Time Frame: all visits (weekly for 12 weeks)
all visits (weekly for 12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Rogosin Institute

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2008

Primary Completion (Actual)

May 1, 2010

Study Completion (Actual)

May 1, 2010

Study Registration Dates

First Submitted

February 24, 2008

First Submitted That Met QC Criteria

February 24, 2008

First Posted (Estimate)

March 4, 2008

Study Record Updates

Last Update Posted (Estimate)

November 24, 2015

Last Update Submitted That Met QC Criteria

October 26, 2015

Last Verified

October 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0712009564

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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