To compare sympathetic and haemostatic activity in rest and after rising in patients with chronic heart failure and healthy subjects, who will be randomly assigned to selective and nonselective beta-blockers. To analyse whether haplotypes of two…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
We will assess two primary endpoints at rest and during exercise: 1.
hypercoagulable activity by platelet function and thrombin generation; 2.
sympathetic activity by plasma (nor)adrenalin concentration, spectral analysis
of blood pressure and heart rate variability. And in patients with heart
failure by 123I-MIBG scinitigraphy.
Secondary outcome
1. Changes in coagulation factors;
2. Changes in fibrinolysis;
3. Cardiac output as calculated by Finapres (BMEYE ABM 100 HD);
4. Central blood pressure as measured by Sphygmocor;
5. Patient*s satisfaction with the two different treatments by using a
questionnaire.
Background summary
Chronic heart failure is common and has a poor prognosis. Therapy with
beta-adrenergic antagonists (beta-blockers) reduces mortality among patients
with heart failure, but guidelines do not differentiate between selective and
non-selective beta-blockers. In heart failure patients, sympatho-adrenergic
activity is increased at rest and frequently excessive during exercise, which
may lead to cardiovascular death, partly due to a hypercoagulable state induced
by this activity. Previous studies have suggested that the release of
norepinephrine is partly regulated by prejunctional beta2-adrenergic receptors.
This implies that non-selective beta-blockers may have a specific
sympathoinhibitory effect that is not present in selective beta1-blockers.
Indeed, in the COMET trial, carvedilol, a non-selective beta-blocker, reduced
cardiovascular mortality in patients with heart failure compared to the
selective beta1-blocker metoprolol. This beneficial effect of carvedilol may be
partially explained by a reduced hypercoagulable response upon sympathetic
activation. Some (small) studies found that these effects could be completely
blocked by propranolol but not by metoprolol or phentolamine, which points to a
beta2-adrenergic specific effect.
Another potential influence on survival in chronic heart failure patients
receiving beta-blockers may be highly prevalent functional beta2-adrenergic
polymorphisms that have been shown to mediate survival in patients with acute
coronary syndrome. Variants of the beta2-adrenergic receptor may be of crucial
importance of the response to beta-blocker therapy by interfering with both
sympathetic activity and hypercoagulable state.
Hypothesis: Sympatho-adrenergic and hypercoagulable activity are enhanced in
patients with chronic heart failure, partially mediated by common functional
beta2-adrenergic polymorphisms. Non-selective beta-blockers down regulate
sympathetic activation via a beta2-adrenergic receptor specific effect. The net
effect is a reduced haemostatic response which will reduce cardiovascular
mortality.
Study objective
To compare sympathetic and haemostatic activity in rest and after rising in
patients with chronic heart failure and healthy subjects, who will be randomly
assigned to selective and nonselective beta-blockers. To analyse whether
haplotypes of two common functional beta2-adrenergic polymorphisms mediate the
sympathetic and haemostatic response before and after beta-blockade.
Study design
Patients with chronic heart failure and healthy controls will be screened for
the two beta2-adrenergic polymorphisms. Patients and controls homozygous for
the Arg16/Gln27 or the Gly16/Glu27 will be tested for hypercoagulable (defined
as platelet response and thrombin generation) and sympathetic activity at rest
and after standing, repeated during an open cross-over design with blinded
endpoints in which these subjects will be randomly assigned to either
carvedilol (a non-selective beta1 and beta2-blocker) or metoprolol (a selective
beta1-blocker) for six weeks.
Intervention
In an open randomised crossover with blinded endpoints trial patients and
healthy volunteers will receive carvedilol BID or metoprolol retard once daily.
Conform guidelines, heart failure patients are already prescribed beta-blockers
on maximal tolerated doses and will be converted to an equipotent dose of the
trial medicine. Equipotency will be guided by the heart rate. There will be a
minimum of four weeks of maximal beta-blocker treatment in both arms. Depending
on the time needed for titration, the total duration of beta-blocker treatment
can range from 6 to 8 weeks.
The target dose for healthy volunteers will be equal to the average dose in
heart failure patients. Target dose for healthy volunteers will be reached in
one week and administered for six weeks. Hereafter subjects crossover to the
alternative arm: those having received carvedilol will receive metoprolol and
vice versa. There is a wash-out period of 4 weeks in between for healthy
volunteers.
Study burden and risks
In total, the study will take 20 weeks for healthy volunteers and 24 weeks for
patients with heart failure. During this period study participants will be
asked to visit the hospital 9 resp 6 times. Visits will last approximately
10-60 minutes (depending on type of visit). During this period 5 blood samples
are taken. There is large experience with carvedilol and metoprolol that have
shown the safety of this medication in the treatment of patients with heart
failure. Current guidelines recommend the use of beta-blockers in patients with
heart failure. The risks associated with this study for patients with heart
failure consist of possible side effects to beta-blocker therapy and will be
equal to normal treatment. Besides, due to small differences between
beta-blockers, temporary worsening of heart failure is possible. Therefore
patients will be monitored closely and medication will be tapered or ceased if
needed.
For healthy volunteers the risks of the study also consist of possible side
effects. These risks are considered low, since healthy volunteers will be
closely monitored with predefined stop criteria and the low cardiovascular risk
of participating healthy individuals.
In patients with heart failure we will also perform a MIBG-scan at the end of
each treatment period. The risk of this diagnostic test is related to the dose
of radiation and is within international limits as they are formulated for
subjects volunteering in research.
Measuring sympathetic activity is of crucial importance in our study and
spectral analysis of blood pressure and heart rate variability is an indirect
measure of sympathetic activity. Besides, spectral analysis could be difficult
to perform since patients with heart failure may have many extra systoles,
which interfere with the calculation used in spectral analysis. Furthermore,
noradrenalin and adrenalin serum levels only indirectly reflect sympathetic
activity.
Therefore, in patients with heart failure, myocardial sympathetic activity will
also be assessed with 123I- meta-iodobenzylguanidine (MIBG) after each
treatment period. MIBG is an aralkylguanidine and shows many similarities with
the neurotransmitter norepinephrine. MIBG, in analogy to catecholamines, is
primarily removed from the circulation by the pre-synaptic nerve endings and
stored in the pre-synaptic storage vesicles. The labelling of MIBG with 123I
allows for the scintigraphic assessment of sympathetic activity.
Semi-quantitative parameters of myocardial 123I-MIBG uptake have been shown to
have independent prognostic and diagnostic value.19,20 Differences in uptake
after each treatment can therefore also be correlated with a prognostic
difference, which will make this study more valuable.
Meibergdreef 9
1105 AZ Amsterdam
Nederland
Meibergdreef 9
1105 AZ Amsterdam
Nederland
Listed location countries
Age
Inclusion criteria
Patients
1. Between 18 and 80 years of age, competent and willing of giving informed consent;
2. With stable symptoms of chronic heart failure (NYHA II-III);
3. With left ventricular ejection fraction *40%, measured within the previous 6 months; if the ejection fraction is not determined, a left-ventricular end diastolic diameter of greater then 6.0 cm and a fractional shortening of less than 20% as measured by echocardiography;
4. With sinusrhythm; (necessary to perform spectral analysis);
5. On stable medical therapy with ACE-inhibitors for at least three months, unless contraindicated; otherwise angiotensin receptor blockers (ARBs);
6. Already on beta-blocker therapy with maximal tolerated doses;;And healthy subjects between 18 and 80 years of age serve as controls to compare sympathetic and hypercoagulable activity with heart failure patients.
Exclusion criteria
Excluded are patients
1. With a history of adverse reaction on beta-blockers;
2. With a contraindication to *-blocker therapy (Sick-sinussyndrome, second and third AV-block), severe hypotension (systolic blood pressure < 100 mm Hg), cardiogenous shock, clinical relevant sinusbradycardia. Asthma, COPD. Liverfunctiondisorder (defined as elevation of aspartamine transaminase, alanine transaminase or bilirubin levels more than three times upper limit of normal range), renal disease (calculated creatinine clearance <50ml/min; using Cockcorft's formula).Insulin dependent diabetes mellitus.);
3. With an acute coronary syndrome or myocardial revascularisation within the preceding 3 months;
4. Who are using anticoagulant therapy. Aspirin is allowed;
5. With severe aortic or mitral valve disease or aortic regurgitation;
6. With right ventricle failure;
7. Requirement for intravenous inotropic therapy, current treatment with calcium channel blockers (of the diltiazem or verapamil class), amiodaron (>200mg per day) or class-I antiarrhythmic drugs, or administration of any investigational drug in the preceding 30 days.
8. Uncontrolled hypertension (blood pressure systolic >170 mmHg or diastolic >105mmHg),
9. Symptomatic and sustained ventricular arrhythmias within the preceding two months not adequately treated with antiarrhythmic drugs or without implantation of an automatic defibrillator;
10. With implanted pacemaker (necessary for spectral analysis); ICD is allowed
11. Pregnancy and women with childbearing potential on inadequate contraception
12. Known drug or alcohol misuse
13. Poor compliance with treatment
14. Any other serious systemic disease that might complicate management and reduce life expectancy.
15. With a known allergy for Iodine;Excluded are healthy controls
1. Taking any medication that will affect our outcome measurements for at least 2 weeks before entering the study
2. With a history of adverse reaction on beta-blockers
3. With a contraindication to beta-blocker therapy as described for patients with heart failure
4. With pregnancy and women with childbearing potential on inadequate contraception
5. Known drug or alcohol misuse
6. Known with poor compliance with treatment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-001994-27-NL |
| Other | Het Nederlands Trial Register (Volgt nog) |
| CCMO | NL18547.018.07 |