Combined Renin Inhibition/Beta-blockade

This study has been terminated.
(The renin laboratory used in the study is no longer available.)
Sponsor:
Information provided by (Responsible Party):
The Rogosin Institute
ClinicalTrials.gov Identifier:
NCT00627861
First received: February 24, 2008
Last updated: September 30, 2011
Last verified: September 2011
  Purpose

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 Intervention
Hypertension
Drug: Aliskiren
Drug: Extended-release metoprolol

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Renin System Responses to Combined Renin Inhibition and Beta Adrenergic Blockade

Resource links provided by NLM:


Further study details as provided by The Rogosin Institute:

Primary Outcome Measures:
  • Plasma Renin Concentration [ Time Frame: 5th, 6th, 7th, 9th, 10th, 11th, 12th weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma Renin Activity [ Time Frame: screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks ] [ Designated as safety issue: No ]
    The blood test, plasma renin activity or PRA, is being measured during the visits outlined.

  • Blood Pressure [ Time Frame: all visits (weekly for 12 weeks) ] [ Designated as safety issue: Yes ]

Enrollment: 1
Study Start Date: November 2008
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    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 Name: 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 Name: Toprol-XL
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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00627861

Locations
United States, New York
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
  More Information

Publications:
Responsible Party: The Rogosin Institute
ClinicalTrials.gov Identifier: NCT00627861     History of Changes
Other Study ID Numbers: 0712009564
Study First Received: February 24, 2008
Results First Received: August 19, 2011
Last Updated: September 30, 2011
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Metoprolol
Metoprolol succinate
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 17, 2014