Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Vanderbilt University
Sponsor:
Collaborators:
University of Washington
Information provided by (Responsible Party):
Alp Ikizler, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00878969
First received: April 8, 2009
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Oxidative Stress
Endothelial Dysfunction
Drug: ramipril (ACE inhibitor)
Drug: valsartan (ARB)
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Health Services Research
Official Title: Genes, Fibrinolysis and Endothelial Dysfunction- Dialysis Aim 3

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • To compare the long term effects of ACE inhibition or angiotensin receptor blockade versus placebo on biomarkers of fibrinolysis, oxidative stress and inflammation in patients with chronic kidney disease undergoing maintenance hemodialysis [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To compare the long term effects of ACE inhibition or AT1 receptor blockade versus placebo on carotid intima-media thickness (IMT) in patients with chronic kidney disease undergoing maintenance hemodialysis [ Time Frame: ongoing ] [ Designated as safety issue: Yes ]
  • Track safety endpoints- hyperkalemia, hypotension, nonfatal myocardial infarction, nonfatal stroke, death from cardiac causes, fatal stroke, death due to any cause. [ Time Frame: ongoing ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 210
Study Start Date: January 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
Drug: ramipril (ACE inhibitor)
Subjects will be randomized to ramipril 2.5 mg/d for one week followed by 5 mg/day for 18 months.
Other Name: Altace
Active Comparator: 2
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
Drug: valsartan (ARB)
Subjects will be randomized to receive Valsartan 80 mg/d for one weeks followed by Valsartan 160 mg/d for 18 months
Other Name: Diovan
Placebo Comparator: 3
If on a ACE or ARB,subjects will first undergo a three week washout period, the subjects will be randomized to take one of three treatments, ramipril, valsartan or placebo.
Drug: Placebo
Subjects will be randomized to receive a placebo for 18 months
Other Name: Inactive pill

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 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, 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  • AIDS (HIV seropositivity is not an exclusion criteria)
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00878969

Contacts
Contact: Brigitta Brannon 615-343-1218 brigitta.brannon@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Jorge Gamboa, MD, PhD    615-343-6479    jorge.gamboa@vanderbilt.edu   
Principal Investigator: Nancy J Brown, MD         
Principal Investigator: Talat A Ikizler, MD         
Sub-Investigator: Jorge Gamboa, MD, PhD         
Sponsors and Collaborators
Vanderbilt University
University of Washington
Investigators
Principal Investigator: Nancy J Brown, MD Vanderbilt University
Principal Investigator: Talat A Ikilzer, MD Vanderbilt University
Principal Investigator: Jonathan Himmelfarb, MD University of Washington
  More Information

No publications provided

Responsible Party: Alp Ikizler, Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00878969     History of Changes
Other Study ID Numbers: Fibrinolysis in Dialysis Aim 3, R01 HL065193-08A2
Study First Received: April 8, 2009
Last Updated: July 22, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Hemodialysis
fibrinolysis
oxidative stress
systemic inflammatory reaction
endothelial dysfunction
carotid intima media thickness (IMT
angiotensin receptor blockade
angiotensin converting enzyme inhibition

Additional relevant MeSH terms:
Angiotensin-Converting Enzyme Inhibitors
Ramipril
Valsartan
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on August 28, 2014