MODIfY is a prospective, single center, open label, randomized, controlled two arms, Phase II-trial to evaluate the ability of ivabradine to reduce an elevated heart rate in Multiple Organ Dysfunction Syndrome (MODS) patients. The primary end point is the proportion of patients with a reduction of heart rate by at least 10 beats per minute (bpm) within 4 days. This trial will randomize 70 patients (men and women, aged ≥ 18 years) with newly diagnosed MODS (Acute Physiology and Chronic Health Evaluation (APACHE) II-score ≥ 20, diagnosis within ≤ 24 hours), with an elevated heart rate (sinus rhythm with HR ≥ 90 bpm) and contraindications to beta-blockers (BBs). Treatment period will last 4 days. All patients will be followed for up to six months.
Background: Heart rate (HR) is of relevant prognostic value not only in the general population and patients with cardiovascular disease but also in critically ill patients with multiple organ dysfunction syndrome (MODS). A raised heart rate in MODS patients is associated with a worse prognosis. Beta-blocker (BB) administration showed to improve autonomic function and exhibited a significantly reduced mortality in MODS. In most cases negative inotropic effects prevent administration of BB in MODS patients which often are treated with catecholamines. In this trial we investigate, whether the "funny current" (If) inhibitor ivabradine is able to reduce pathologically elevated heart rate in MODS- patients. The investigators hypothesized that critically ill patients could derive particular benefit from the specific HR-lowering agent ivabradine. Methods: MODIfY is a prospective, single center, open label, randomized, controlled two arms, Phase II-trial to evaluate the ability of ivabradine to reduce an elevated heart rate in MODS patients. The primary end point is the proportion of patients with a reduction of heart rate by at least 10 beats per minute (bpm) within 4 days. This trial will randomize 70 patients (men and women, aged ≥18 years) with newly diagnosed MODS (Acute Physiology and Chronic Health Evaluation (APACHE) II-score ≥20, diagnosis within ≤24 hours), with an elevated heart rate (sinus rhythm with HR ≥90 bpm) and contraindications to BBs. Treatment period will last 4 days. All patients will be followed for up to six months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
Patients in the ivabradine treatment arm receive an additional enteral preparation (orally, via nasogastric tube or percutaneous endoscopic gastrostomy-probe) of ivabradine for 4 days. Day 1 and 2: 5,0 mg ivabradine b.i.d. if heart rate ≥60bpm (acute renal failure: ≥70bpm) Day 3 and 4: 5,0 mg ivabradine b.i.d. if 60bpm≥heart rate\<90bpm (acute renal failure: 70bpm≥heart rate \<90bpm 7,5 mg ivabradine b.i.d. if heart rate ≥90bpm
Department of Medicine III of the University Clinics Halle (Saale) of the Martin-Luther-University Halle-Wittenberg
Halle, Saxony-Anhalt, Germany
RECRUITINGmean heart rate
percenage of patients with a reduction of the mean heart rate of at least 10 bpm 96 hours after the start of trial treatment
Time frame: 4 days
morbidity
group-differences and patient-related changes of morbidity measured by serial APACHE II score monitoring and Sequential Organ Failure Assessment (SOFA) score monitoring
Time frame: 4 days
hemodynamic parameters
group-differences and patient-related changes of hemodynamic parameters (cardiac index and cardiac power index) as a consequence of ivabradine treatment
Time frame: 4 days
catecholamine dosage
required catecholamine dosage measured by a vasopressor score
Time frame: 4 days
microcirculation
improvement of microcirculation as measured by sublingual capillary density and flow
Time frame: 4 days
endothelial function
improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
Time frame: 4 days
mean heart rate
comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
Time frame: 48 hours
mortality
28-day and 6 months mortality
Time frame: 6 months
cardiac autonomic dysfunction
impact on cardiac autonomic dysfunction (heart rate variability quantified by time domain measurements (standard deviation of normal to normal interval (SDNN)) and frequency domain measurements (very low frequency (VLF)-, high frequency (HF)- and low frequency (LF)-power) as well as minimum, maximum, day and night heart rate)
Time frame: 4 days
number of participants with adverse events as a measure of safety and tolerability
Time frame: 6 months
plasma levels of ivabradine in patients with MODS
daily measurement of plasma levels during the treatment period (4 days)
Time frame: 4 days
Differences of mortality in different age groups and MODS groups
age sub-groups: 1. patients \<70 years on day of inclusion 2. patients ≥70 years on day of inclusion MODS sub-groups: 1. patients with cardiogenic MODS 2. patients with septic MODS
Time frame: 6 months
Differences of adverse events in different age groups and MODS groups
age sub-groups: 1. patients \<70 years on day of inclusion 2. patients ≥70 years on day of inclusion MODS sub-groups: 1. patients with cardiogenic MODS 2. patients with septic MODS
Time frame: 6 months
Differences of heart rate in different age groups and MODS groups
age sub-groups: 1. patients \<70 years on day of inclusion 2. patients ≥70 years on day of inclusion MODS sub-groups: 1. patients with cardiogenic MODS 2. patients with septic MODS
Time frame: 6 months
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