Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

NCT ID: NCT00878969

Last Updated: 2016-02-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-31
• Study Completion Date: 2015-06-30

Brief Summary

The purpose of the study is to see how two classes of blood pressure medications,angiotensin-converting enzyme inhibitors (Ace inhibitors) and angiotensin receptor blockers (ARBs), differ in their long term effects on certain chemicals in the body and on the carotid arteries.

Detailed Description

More than 400,000 individuals with chronic kidney disease undergo hemodialysis each year in the United States. Atherosclerotic cardiovascular disease is the leading cause of mortality in these patients. Conventional risk factors for coronary artery disease (CAD) do not adequately explain this increased mortality, whereas biomarker of oxidative stress and inflammation correlate with clinical outcomes. Even with the use of biocompatible membranes, hemodialysis induces a systemic inflammatory reaction characterized by complement activation, leukocyte activation and the generation of reactive oxygen species and cytokines. Oxidative stress and inflammation promote endothelial dysfunction, a predictor of atherosclerotic cardiovascular events.

The purpose of the study is to test the hypothesis that angiotensin-converting enzyme inhibition and angiotensin receptor blockade differ in their long term effects on biomarkers of fibrinolysis, oxidative stress,inflammation and on carotid intima-media thickness (IMT), a predictor of cardiovascular events, in patients with chronic kidney disease undergoing maintenance hemodialysis.

Endogenous Bradykinin (BK) contributes to the hypotensive and pro-fibrinolytic effects of ACE inhibitors. It has been determined that endogenous BK contributes to the vasodilator effects of acute and chronic ACE inhibition. Studies have found that BK stimulates vascular tissue plasminogen activator (t-PA) release through a BK B2 receptor-dependent, nitric oxide (NO) and cyclooxygenase-independent pathway. Hemodialysis patients demonstrates endothelial dysfunction. Data suggests that t-PA release may be attenuated during stimulation of the endogenous kallikrein-kinin system by hemodialysis.

Intra-arterial infusion of BK increases vascular release of F2- isoprostanes, markers of oxidative stress, BK infusions also increase net release of the inflammatory cytokine interleukin-6 (IL-6). Preliminary data raise the possibility that activation of the endogenous kallikrein-kinin system during dialysis could promote inflammation in individuals with chronic kidney disease who are treated with an ACE inhibitor.

Cardiopulmonary bypass activates the endogenous kallikrein-kinin system and causes a systemic inflammatory response. Like hemodialysis, cardiopulmonary bypass activates the endogenous kallikrein-kinin system, increasing BK concentrations. In smokers, who like hemodialysis patients exhibit endothelial dysfunction, the t-PA response to BK was attenuated during cardiopulmonary bypass.

ACE inhibition enhances fibrinolysis and decreases inflammation following cardiopulmonary bypass. The short-term effect of both ACE inhibition and angiotensin II type 1 (AT1) receptors on markers of fibrinolysis and inflammation during dialysis are currently being studied.

Circulating BK concentrations are increased during hemodialysis in individuals treated with an ACE inhibitors compared to those treated with an AT1 receptor blocker.

Bradykinin receptor blockade and the fibrinolytic and inflammatory response to hemodialysis. It is hypothesized that subjects with CAD, the t-PA response to hemodialysis will be blunted compared to that measured in subjects without evidence of CAD, whereas the inflammatory response wil be similar or enhanced.

Conditions

Oxidative Stress; Endothelial Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: QUADRUPLE

Study Groups

Valsartan

80 mg of valsartan (ARB) taken orally on a daily basis for 1 week followed by 160 mg of valsartan taken orally on a daily basis for 18 months

Group Type: ACTIVE_COMPARATOR

valsartan (ARB)

Intervention Type: DRUG

Ramipril

2.5 mg of ramipril (ACE inhibitor) taken orally on a daily basis for 1 week followed by 5 mg of ramipril taken orally on a daily basis for 18 months

Group Type: ACTIVE_COMPARATOR

ramipril (ACE inhibitor)

Intervention Type: DRUG

Placebo

matching placebo taken orally on a daily basis for 1 week followed by matching placebo taken orally on a daily basis for 18 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

valsartan (ARB)

Intervention Type: DRUG

ramipril (ACE inhibitor)

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Diovan; Altace; Inactive pill

Eligibility Criteria

Inclusion Criteria

• Age 18 years or older
• On thrice weekly chronic hemodialysis for at least 6 months
• Clinically stable, adequately dialyzed [single-pool Kt/V > 1.2 or Urea Reduction Ratio (URR) > 65%] thrice weekly, with polysulphone membrane for at least 3 consecutive months prior to study

Exclusion Criteria

• History of functional transplant less than 6 months prior to study
• Use of immunosuppressive drugs within 1 month prior to study
• History of active connective tissue disease
• History of acute infectious disease within one month prior to study
• History of myocardial infarction or cerebrovascular event within 3 months
• Advanced liver disease
• Gastrointestinal dysfunction requiring parental nutrition
• Active malignancy excluding basal cell carcinoma of the skin
• History of ACE inhibitor-associated cough (intolerable) or angioedema
• Ejection fraction less than 30%
• Inability to discontinue ACE inhibitor or ARB
• Predialysis potassium repeatedly higher than 6.0 mmol/L (confirmed on a repeated blood draw)
• Anticipated live donor kidney transplant
• Pregnancy or breast-feeding
• History of poor adherence to hemodialysis or medical regimen
• Inability to provide consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Washington

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Alp Ikizler

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Talat A Ikilzer, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Jonathan Himmelfarb, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

R01HL065193-08A2

Identifier Type: NIH

Identifier Source: secondary_id

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Fibrinolysis in Dialysis Aim 3

Identifier Type: -

Identifier Source: org_study_id