Coronary Artery DiseasePhase 4NCT01768585
Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease
A Phase 4 study testing Ivabradine in people with Coronary Artery Disease and Coronary Arteriosclerosis, run by University Hospital, Saarland at 1 site in Germany.
Trial summary
This study investigates whether chronic heart rate reduction with ivabradine (Procoralan®, Servier, France) affects aortic compliance and endothelial function in patients with chronic stable coronary artery disease. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Coronary Artery Disease, Coronary Arteriosclerosis
- What is being tested?
- Ivabradine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteGermany
- Study dates
- Dec 2012to Dec 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age > 18 years old
- Resting heart rate ≥ 70 bpm
- Sinus rhythm
- Chronic stable coronary artery disease (CAD)
- Coronary artery disease proven by coronary angiography
- Written informed consent to participate in the study
Who cannot join
- Acute coronary syndrome
- CAD treated best by surgical coronary bypass
- Stroke/TIA
- Resting heart rate < 70 bpm
- Indwelling pacemaker or AICD
- Severe valvular heart disease
Show all 18Show fewer
- Any other rhythm than sinus
- Sick-Sinus-Syndrome, SA nodal block, >2nd degree atrio-ventricular block
- Untreated arterial hypertension
- Arterial hypotension (<90/50mmHg)
- Severe hepatic failure
- Heart failure (NYHA class III - IV)
- Patient already treated with study drug
- Symptomatic PAD
- Known diabetes mellitus
- Pre-menopausal women
- Hypersensitivity against ivabradine or adjuvants
- Coexisting drug treatment with Cytochrom P450 3A4-inhibitors
Trial locations and contacts
1 site in 1 country.
Germany1 site, 1 recruiting
- Recruiting
University Hospital, Saarland
Homburg, Saarland, 66421
Florian Custodis, MD, 0049-6841-1623000, Florian.Custodis@uks.eu
Angelika Knoll, 0049-6841-1623412, Angelika.Knoll@uks.eu
About this study
Official title: A Randomised, Placebo Controlled, Double Blind, Cross-over, Single Center Clinical Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease
This study investigates whether chronic heart rate reduction with ivabradine (Procoralan®, Servier, France) affects aortic compliance and endothelial function in patients with chronic stable coronary artery disease.
Read the detailed description
Experimental and clinical data suggest that sustained elevation of heart rate contributes to the pathogenesis of vascular disease (1, 2). In animal studies accelerated heart rate is associated with signalling events leading to vascular oxidative stress, endothelial dysfunction and acceleration of atherogenesis (3). The underlying mechanisms are only partially understood and appear to correlate with mechanic properties such as reduction of vascular compliance. Heart rate reduction by I(f)-channel inhibition with ivabradine (Procoralan®, Servier, France) attenuates oxidative stress, improves endothelial function and reduces the formation of atherosclerotic plaques in mice models of lipid-induced atherosclerosis (1, 4).
Aortic stiffness is a consequence of arterial aging and vascular risk factors and determinates cardiovascular mortality (5). Heart rate depending repetitive pulsations appear to induce fatigue and fracture of elastin lamellae of central arteries. As a result the vessel stiffens and pulse wave reflections return earlier to the heart. In consequence aortic pressure rises and pulsations of flow extend further into smaller vessels of organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased hemodynamic stresses on small arterial vessels.
Several experimental investigations revealed an interaction between heart rate and vascular compliance demonstrating a positive association between increased heart rate and arterial stiffness (6). Recent experimental data suggest that heart rate reduction by ivabradine (Procoralan®, Servier, France) significantly improves aortic distensibility in cholesterol fed ApoE -/- mice measured by MRI technique (7). While a benefit of pharmacological heart rate reduction on vascular outcomes was observed in animal studies, prospective clinical data are limited and evidence determining whether chronic modulation of heart rate can improve vascular function and compliance in patients with chronic stable coronary artery disease is needed.
- Conditions
- Coronary Artery Disease, Coronary Arteriosclerosis
- Being tested
- Ivabradine, Placebo
- Medical subject headings
- Coronary Artery Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IvabradineDrug
Also called Procoralan
Please see description of Intervention Arm
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Ivabradine | Active comparator | Drug: Ivabradine bid administration of 7.5mg ivabradine Other Name: Procoralan, I(f)-inhibitor Receives: Drug: Ivabradine |
| Placebo | Placebo comparator | Drug: Placebo bid placebo Other Name: Placebo control Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis)
Measured: Decembre 2014
Secondary outcomes (1)
Biomarkers (inflammation, oxidative stress)
Measured: Decembre 2014
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jan 2013 (estimated)
- Study startDec 2012
- Primary completionDec 2014 (estimated)
- Study completionDec 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Saarland
- Sponsor type
- University, hospital or other
- Collaborators
- Universität des Saarlandes
- Responsible party
- Sponsor
- Investigators
- Ulrich Laufs, Principal investigator, Saarland University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01768585
- Sponsor's protocol ID
- HomRate04_2012
- Status last verified
- Jan 2013
- First submitted
- 11 Jan 2013
- Last updated
- 15 Jan 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Custodis F, Baumhakel M, Schlimmer N, List F, Gensch C, Bohm M, Laufs U. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008 May 6;117(18):2377-87. doi: 10.1161/CIRCULATIONAHA.107.746537. Epub 2008 Apr 28.
PubMed 18443241Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984 Oct 12;226(4671):180-2. doi: 10.1126/science.6484569.
PubMed 6484569Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010 Dec 7;56(24):1973-83. doi: 10.1016/j.jacc.2010.09.014.
PubMed 21126638Noels H, Weber C. Fractalkine as an important target of aspirin in the prevention of atherogenesis : Editorial to: "Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice" by H. Liu et al. Cardiovasc Drugs Ther. 2010 Feb;24(1):1-3. doi: 10.1007/s10557-009-6213-4. No abstract available.
PubMed 20033269Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol. 2011 Apr 5;57(14):1511-22. doi: 10.1016/j.jacc.2010.12.017.
PubMed 21453829Mangoni AA, Mircoli L, Giannattasio C, Ferrari AU, Mancia G. Heart rate-dependence of arterial distensibility in vivo. J Hypertens. 1996 Jul;14(7):897-901. doi: 10.1097/00004872-199607000-00013.
PubMed 8818929Custodis F, Fries P, Muller A, Stamm C, Grube M, Kroemer HK, Bohm M, Laufs U. Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein E-deficient mice. J Vasc Res. 2012;49(5):432-40. doi: 10.1159/000339547. Epub 2012 Jul 3.
PubMed 22759927
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Placebo Controlled, Double Blind, Cross-over, Single Center Clinical Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease
- ClinicalTrials.gov ID
- NCT01768585
- Acronym / sponsor ID
- HomRate04_2012
- Conditions
- Coronary Artery Disease, Coronary Arteriosclerosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- University Hospital, SaarlandUniversity, hospital or other
- Collaborators
- Universität des Saarlandes
- Study start
- Dec 2012
- Primary completion
- Dec 2014 (estimated)
- Study completion
- Dec 2014 (estimated)
- First posted
- 15 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study investigates whether chronic heart rate reduction with ivabradine (Procoralan®, Servier, France) affects aortic compliance and endothelial function in patients with chronic stable coronary artery disease.
Detailed description
Experimental and clinical data suggest that sustained elevation of heart rate contributes to the pathogenesis of vascular disease (1, 2). In animal studies accelerated heart rate is associated with signalling events leading to vascular oxidative stress, endothelial dysfunction and acceleration of atherogenesis (3). The underlying mechanisms are only partially understood and appear to correlate with mechanic properties such as reduction of vascular compliance. Heart rate reduction by I(f)-channel inhibition with ivabradine (Procoralan®, Servier, France) attenuates oxidative stress, improves endothelial function and reduces the formation of atherosclerotic plaques in mice models of lipid-induced atherosclerosis (1, 4).
Aortic stiffness is a consequence of arterial aging and vascular risk factors and determinates cardiovascular mortality (5). Heart rate depending repetitive pulsations appear to induce fatigue and fracture of elastin lamellae of central arteries. As a result the vessel stiffens and pulse wave reflections return earlier to the heart. In consequence aortic pressure rises and pulsations of flow extend further into smaller vessels of organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased hemodynamic stresses on small arterial vessels.
Several experimental investigations revealed an interaction between heart rate and vascular compliance demonstrating a positive association between increased heart rate and arterial stiffness (6). Recent experimental data suggest that heart rate reduction by ivabradine (Procoralan®, Servier, France) significantly improves aortic distensibility in cholesterol fed ApoE -/- mice measured by MRI technique (7). While a benefit of pharmacological heart rate reduction on vascular outcomes was observed in animal studies, prospective clinical data are limited and evidence determining whether chronic modulation of heart rate can improve vascular function and compliance in patients with chronic stable coronary artery disease is needed.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ivabradine | Active comparator | Drug: IvabradineDrug: Ivabradine bid administration of 7.5mg ivabradine Other Name: Procoralan, I(f)-inhibitor |
| Placebo | Placebo comparator | Drug: PlaceboDrug: Placebo bid placebo Other Name: Placebo control |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Age > 18 years old
- Resting heart rate ≥ 70 bpm
- Sinus rhythm
- Chronic stable coronary artery disease (CAD)
- Coronary artery disease proven by coronary angiography
Key exclusion criteria (18 listed)
- Acute coronary syndrome
- CAD treated best by surgical coronary bypass
- Stroke/TIA
- Resting heart rate < 70 bpm
- Indwelling pacemaker or AICD
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IvabradineAlso: ProcoralanPlease see description of Intervention Arm | Drug | Ivabradine |
| Placebo | Drug | Placebo |
Primary outcome
Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis)
Time frame: Decembre 2014
1 secondary outcome
Biomarkers (inflammation, oxidative stress)
Time frame: Decembre 2014
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2013.
- Background: PubMed 18443241Custodis F, Baumhakel M, Schlimmer N, List F, Gensch C, Bohm M, Laufs U. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008 May 6;117(18):2377-87. doi: 10.1161/CIRCULATIONAHA.107.746537. Epub 2008 Apr 28.
- Background: PubMed 6484569Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984 Oct 12;226(4671):180-2. doi: 10.1126/science.6484569.
- Background: PubMed 21126638Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010 Dec 7;56(24):1973-83. doi: 10.1016/j.jacc.2010.09.014.
- Background: PubMed 20033269Noels H, Weber C. Fractalkine as an important target of aspirin in the prevention of atherogenesis : Editorial to: "Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice" by H. Liu et al. Cardiovasc Drugs Ther. 2010 Feb;24(1):1-3. doi: 10.1007/s10557-009-6213-4. No abstract available.
- Background: PubMed 21453829Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol. 2011 Apr 5;57(14):1511-22. doi: 10.1016/j.jacc.2010.12.017.
- Background: PubMed 8818929Mangoni AA, Mircoli L, Giannattasio C, Ferrari AU, Mancia G. Heart rate-dependence of arterial distensibility in vivo. J Hypertens. 1996 Jul;14(7):897-901. doi: 10.1097/00004872-199607000-00013.
- Background: PubMed 22759927Custodis F, Fries P, Muller A, Stamm C, Grube M, Kroemer HK, Bohm M, Laufs U. Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein E-deficient mice. J Vasc Res. 2012;49(5):432-40. doi: 10.1159/000339547. Epub 2012 Jul 3.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ulrich Laufs principal investigator
Saarland University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ivabradine in people with Coronary Artery Disease and Coronary Arteriosclerosis, run by University Hospital, Saarland at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 15 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Florian Custodis, MD (0049-6841-1623000, Florian.Custodis@uks.eu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis) (time frame: Decembre 2014). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01768585, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2013.