Combined Renin Inhibition/Beta-blockade

Hypertension Clinical Trial

Official title:

Renin System Responses to Combined Renin Inhibition and Beta Adrenergic Blockade

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00627861
• Other study ID #: 0712009564
• Status: Terminated
• Phase: N/A
• First received: February 24, 2008
• Last updated: October 26, 2015
• Start date: November 2008
• Est. completion date: May 2010

Study information

• Verified date: October 2015
• Source: The Rogosin Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 a2-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 ß-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 Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension

Intervention

Drug:
• Aliskiren
150mg orally daily for 6 weeks. Dose may increase to 300mg orally daily dependent upon blood pressure parameters set by the protocol.
• 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.

Locations

Country	Name	City	State
United States	The Rogosin Institute	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
The Rogosin Institute

Country where clinical trial is conducted

United States, 

References & Publications (5)

Blumenfeld JD, Sealey JE, Mann SJ, Bragat A, Marion R, Pecker MS, Sotelo J, August P, Pickering TG, Laragh JH. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hyperte — View Citation

Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002 Jan;39(1):E1-8. — View Citation

Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007 Jul 21;370(9583):221-9. Erratum in: Lancet. 2007 Nov 3;37 — View Citation

Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens. 2007 May;20(5):587-97. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma Renin Concentration		5th, 6th, 7th, 9th, 10th, 11th, 12th weeks	No
Secondary	Plasma Renin Activity	The blood test, plasma renin activity or PRA, is being measured during the visits outlined.	screening, 4th, 6th, 7th, 9th, 10th, 11th, 12th weeks	No
Secondary	Blood Pressure		all visits (weekly for 12 weeks)	Yes