Informations générales (source: ClinicalTrials.gov)
A Multicenter, Prospective, Randomized, Placebo-controlled, Double-blind, Multi-arm, Multi-stage Clinical Trial of Ivabradine for Heart Rate Control In Septic Shock
Interventional
Phase 3
Assistance Publique - Hôpitaux de Paris (Voir sur ClinicalTrials)
février 2021
décembre 2024
13 septembre 2025
Septic shock is a major health problem, with several million cases annually worldwide and
a mortality approaching 45%. Tachycardia is associated with excess mortality during
septic shock. This pejorative effect could be related to the increase in cardiac
metabolic demand, impaired cardiac diastolic function, and/or poorer tolerance of
administered exogenous catecholamines. Recent studies suggest that controlling the heart
rate with the use of beta blockers has beneficial effects on the morbidity and mortality
of septic shock. However, the negative effects of beta-blockers on cardiac contractility
and blood pressure complicate their use during septic shock, particularly because about
one-half of patients exhibit a septic-associated systolic dysfunction, which often
requires the use of inotropes.
Ivabradine is a selective inhibitor of If channels in the sinoatrial node. It is a pure
bradycardic agent with no deleterious effect on other aspects of cardiac function
(contractility, conduction and repolarization) nor on blood pressure. Ivabradine can
therefore alleviate sinus tachycardia without negative inotropic effects nor hypotension.
Moreover, the improvement in diastolic function (ventricular filling) with ivabradine may
increase stroke volume, even in case of severe impairment of systolic function.
Controlling sinus tachycardia with ivabradine during septic shock would allow reducing
cardiac metabolic demand (and potentially associated ischemic events) and improving the
chronotropic tolerance of exogenous catecholamines. The effectiveness of ivabradine in
controlling the heart rate was demonstrated in various clinical settings such as coronary
artery disease, chronic heart failure and cardiogenic shock. Encouraging preliminary data
are reported in critically ill patients.
Etablissements
Critères
Tous
Inclusion Criteria:
- 18 years of age or older,
- Proven or suspected site of infection,
- Septic shock (defined as hypotension unresponsive to fluid resuscitation and
requiring vasopressor treatment to maintain adequate blood pressure in the context
of proven or suspected site of infection) for at least 2 hours and less than 24
hours (inclusion is possible before 2 hours in case of increasing doses of
norepinephrine),
- In sinus rhythm with heart rate ≥ 95 bpm at time of randomization,
- Informed consent obtained in accordance with local regulations,
- Affiliation to a social security regime.
- 18 years of age or older,
- Proven or suspected site of infection,
- Septic shock (defined as hypotension unresponsive to fluid resuscitation and
requiring vasopressor treatment to maintain adequate blood pressure in the context
of proven or suspected site of infection) for at least 2 hours and less than 24
hours (inclusion is possible before 2 hours in case of increasing doses of
norepinephrine),
- In sinus rhythm with heart rate ≥ 95 bpm at time of randomization,
- Informed consent obtained in accordance with local regulations,
- Affiliation to a social security regime.
- Age < 18 years,
- Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"),
sino-atrial block; 3rd degree atrioventricular block, "IRISS" protocol, version 6.0
of 30/10/2023 7/47 This document is the property of DRCD / APHP. All reproduction is
strictly prohibited.
- Cardiogenic shock or unstable or acute heart failure without proven or suspected
infection,
- Acute myocardial infarction with angiographic documentation; CCS class
≥ II angina pectoris;
- Septic shock requiring vasopressor treatment for more than 24 hours,
- Refractory shock with systolic arterial pressure <90 mm Hg) despite the use of high
doses of vasopressors (norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min;
these doses should be multiplied by two for noradrenaline salt (tartrate or
bitartrate),
- Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of
CYP4503A4, pacemaker, defibrillator, kalemia <3 mM,
- Co-treatment with verapamil or diltiazem (which are moderate CYP4503A4 inhibitors
with heart rate reducing properties)
- Known pregnancy, breast feeding, women with childbearing potential will be tested
for pregnancy and excluded if pregnant,
- Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa,
congenital galactosemia, lactase deficiency, glucose or galactose malabsorption,
- Severe chronic renal failure (creatinine clearance <15 ml/min) or hepatic failure
(prothrombin time <20%),
- Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency,
glucose-galactose malabsorption syndrome,
- Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL),
- Prior enrolment in the trial, participation in another interventional study on
septic shock,
- Known legal incapacity (patients under guardianship or curatorship),
- Decision to limit full care taken before obtaining informed consent,
- Patient under AME (state emergency medical help),
- Lack of affiliation to social security.