Combined Renin Inhibition/Beta-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 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|
- Plasma Renin Concentration [ Time Frame: 5th, 6th, 7th, 9th, 10th, 11th, 12th weeks ] [ Designated as safety issue: No ]
- 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 ]
|Study Start Date:||November 2008|
|Study Completion Date:||May 2010|
|Primary Completion Date:||May 2010 (Final data collection date for primary outcome measure)|
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00627861
|United States, New York|
|The Rogosin Institute|
|New York, New York, United States, 10021|
|Principal Investigator:||Jon D Blumenfeld, M.D.||The Rogosin Institute|