Download 5-1-16 1 Ivabradine in Sepsis for Heart Rate, Benefits and

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Ivabradine in Sepsis for Heart Rate, Benefits and
Disadvantages trial (IS-HR-BAD)
PROTOCOL Version 6, 5th January 2016
Principal investigator:
Dr Thomas Rozen
(Intensive Care Fellow)
Co-investigators:
A/Prof Andrew Udy
(Consultant Intensivist)
Dr Lloyd Roberts
(Consultant Intensivist)
Dr James Hare
(Consultant cardiologist)
Dr Owen Roodenburg
(Consultant intensivist)
Dr Aidan Burrell
(Consultant Intensivist)
Dr Larissa Douglas
(ICU Senior Registrar)
Ms Bianca Levkovich
(ICU Pharmacist)
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Ivabradine in Sepsis for Heart Rate, Benefits and
Disadvantages trial (IS-HR-BAD)
Aims and objectives
To demonstrate the efficacy and safety of enteral Ivabradine administration in
tachycardic critically ill patients with suspected or confirmed sepsis receiving
vasopressor support.
Primary Aim:
To determine the efficacy and dose-response of a single enteral dose of
Ivabradine to reduce participant heart rate.
Secondary Aims:
To explore the effects of a single enteral dose of Ivabradine on:

Systemic haemodynamics including measures of cardiac output

Vasopressor requirements

Lactate production

Non-cardiovascular organ function, and

Adverse events.
Background and rationale
Sepsis represents a common reason for admission to the ICU, often involving
older people with multiple comorbidities1. These patients often have a prolonged
hospital stay, complicated by multiorgan derangement leading to greater
morbidity and mortality. 2
Typically, patients have a high cardiac output, low resistance circulation with
tachycardia and arterial hypotension3 requiring infusions of vasoconstrictor
medications.
There is an emerging body of evidence that tachycardia in sepsis contributes to
morbidity in some people and can cause numerous complications including
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myocardial infarction, stress cardiomyopathy, immunosuppression and insulin
resistance. 4-6
Tachycardia may contribute to impaired diastolic filling time and at high rates
may actually reduce the cardiac output.
Controlling HR could therefore be beneficial7. While beta-blockers are
traditionally used, they have the potential to influence vasomotor tone which
may worsen the clinical state when noradrenaline is used. Ivabradine is
currently the only agent known to lower heart rate without any negative
inotropism, or effects on conduction and contractility. It’s currently used in heart
failure patients8 to prevent tachycardia, and acts via a novel receptor in the sinus
node to reduce heart rates without impacting on contractility9. The use of
ivabradine in the septic population has been proposed10,11 as a highly novel and
previously untested intervention.
This study aims to evaluate if a single dose of ivabradine is effective at reducing
heart rate in septic patients, without escalation of inotropic or vasopressor
support.
Hypothesis:
Primary Hypothesis:
In tachycardic critically ill patients with suspected or confirmed sepsis receiving
vasopressor support, a single enteral dose of ivabradine will reduce participant
heart rate.
Secondary Hypothesis:
In tachycardic critically ill patients with suspected or confirmed sepsis receiving
vasopressor support, a single enteral dose of ivabradine will:
a)
b)
c)
d)
not significantly alter cardiac output
not result in an increase in plasma lactate concentrations
not be associated with an increase in vasoactive medication requirements
not result any significant side effects
Design and methodology
Study design
We will conduct an open label phase II clinical trial.
Critically ill patients with presumed or confirmed sepsis (defined by the
administration of antibiotics for therapeutic purposes) with sinus tachycardia
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despite fluid resuscitation, and requiring vasopressor support, will receive a
single enteral dose of ivabradine.
Ivabradine pharmacology12:
Ivabradine is a heart rate lowering agent, acting by selective inhibition of the
cardiac pacemaker If current that controls the spontaneous diastolic
depolarisation in the sinus node and regulates heart rate.
The effects are
relatively specific to the sinus node with no effect on intraatrial, artioventricular
or intraventricular conduction times.
Ivabradine is extensively metabolised by the liver and the gut by oxidation
through cytochrome P450 3A4 (CYP3A4) only. Metabolites are excreted in urine
and faeces. Main t ½ is 2 h (70-75% of area under the curve) in plasma and has
an effective t ½ of 11 h. Total clearance is 400 ml/min and renal clearance is 70
ml/min. Ivabradine has been studied in two broadly distinct populations, i.e.
anginal/ ischaemic (nearly 10,000 patients) and congestive cardiac failure
(about 3,200 patients), in clinical trials involving a total of nearly 13,000 patients.
The various adverse effects of ivabradine includes luminous phenomenon (due
to blockade of Ih channel in the retina, which resembles If cardiac channels),
atrioventricular block, ventricular extrasystole and bradycardia. 8,13-15
Outcomes:
Primary:
Reduction in participant heart rate following study drug administration.
Secondary:




Mean arterial pressure, stroke volume, cardiac output (as measured by
pulse-contour analysis and trans-thoracic echocardiography)
Plasma lactate concentrations pre- and post-dose
Non-cardiovascular organ function (as measured by PaO2/FiO2 ratio,
Urine output, renal and liver biochemistry)
Significant adverse events.
Study population and Inclusion criteria
Any patient admitted to the ICU with presumed or confirmed sepsis on
antibiotics, with a sinus tachycardia >100/min.
Inclusion criteria:
1. Age ≥ 18;
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2. Presumed diagnosis of sepsis on intravenous antibiotics;
3. A heart rate of >100/min in sinus rhythm;
4. The requirement for vasopressor infusion to maintain a mean arterial
pressure > 65mmHg despite adequate fluid resuscitation (defined by a
central venous pressure > 8mmHg);
5. Informed consent is obtained from the patient or surrogate decision
maker;
6. The patient is anticipated to require ICU care beyond the next calendar
day; and
7. Presence of an indwelling urinary catheter (IDC) and arterial line
Exclusion criteria:
1.
2.
3.
4.
Pacemaker in situ; or
Use of a beta blocker within the last 48 hours; or
History of rhythm disturbance or bradycardia; or
Concurrent use of inhibitors of CYP3A4 (macrolide antibiotics, azole
antifungals) that interact with the metabolism of ivabradine; or
5. Inability to administer enteral medication; or
6. Severe hepatic dysfunction – defined as an AST or ALT > 5 x upper limit of
normal (ULN), or and AST or ALT > 3 x ULN with an associated total
bilirubin > 2 x ULN; or
7. Pregnancy; or
8. Breast-feeding mothers; or
9. Inability to complete the monitoring period in ICU following ivabradine
administration; or
10. Patient not expected to survive next 24-48 hours and/or clinician not
committed to ongoing life support
Study Procedures:
Study treatment:
Following enrolment and consent, baseline demographic, illness severity,
comorbidity, physiological and therapeutic data will be recorded prior to dosing.
The ability to provide enteral medications will be confirmed by a member of the
study team. Participants will then receive a single enteral dose of 5mg ivabradine.
Hourly haemodynamic variables will then be recorded for the next 12 hours.
Cardiac output and stroke volume measurements will be obtained from a pulsecontour cardiac output monitor (Vigileo®, Edwards Lifesciences). This device is
attached directly to the intra-arterial line, and is entirely non-invasive. Where
possible, a trans-thoracic echocardiogram will be performed prior to and 6hours after study drug administration. These data will be available to the
treating clinician if requested.
Interim analysis will be performed after the first 5 participants have completed
the protocol. Based on the haemodynamic and clinical data obtained, we will
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consider altering either the dose or duration of therapy to more accurately
define the optimum intervention. These data will be reported to the Ethics
committee and any protocol amendment submitted for approval before any
further enrolment.
Follow up Schedule and Data collection:
Haemodynamic monitoring will continue for 12 hours post study drug
administration. The primary outcome will be assessed by the hourly recorded
heart rate. Efficacy will be determined by calculating the mean, maximum, and
minimum heart rate post drug administration, as well as the area under the
curve (AUC) of heart rate versus time.
Cardiac output will be assessed using the Vigileo® monitor +/- trans-thoracic
echocardiogram. Any changes in vasoactive infusions will be obtained from the
medication administration record and/or ICU observation chart. Hourly urine
output and fluid administration will be recorded from the fluid balance record.
Plasma lactate concentrations will be obtained by performing arterial blood gas
sampling at 0, 3, 6 and 12 hours. Renal and liver biochemistry will also be
performed pre- and post-study drug administration.
Data sources
Research coordinators will identify patients during their routine weekday
review of all Intensive Care Unit patients. Therefore, recruitment will be based
on convenience sampling during business hours. Data will be taken from the
patient’s progress notes and ICU observations.
Additional data will be obtained from the hospital clinical information system
databases, and the patient’s scanned medical record.
Details of data collected
1. Baseline demographic data
a. Age
b. Gender
c. Admission diagnosis (as per APACHE III diagnostic criteria)
d. Apache III score (will require cross referencing with AORTIC/HIS
databases)
2. Co-morbidities
a. Documented history in the medical record
3. Physiological and biochemical derangements in ICU at enrolment.
a. Derangements in vital signs (Worst value in last 12hr)
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i. Hypoxemia (SpO2 %), increased respiratory rate or minute
ventilation (L/min)
ii. Hypotension (MAP in mmHg) or tachycardia (bpm)
iii. Oliguria (ml in 4hr)
b. Electrolyte, Arterial Blood Gas – worst value, prior 12 hr
i. Elevations in serum lactate
ii. Derangements in K+, Mg++, Ca ++
iii. Worsening urea or creatinine
4. Changes in Intensive Care supports prior to enrollment (highest value
and max change in last 12 hr):
a. Vasopressor/inotrope levels
b. Requirements for invasive and non-invasive respiratory support
c. Renal Replacement Therapy (RRT) in the 24 hours preceding
5. Haemodynamic and physiological variables post-dose
a. Hourly heart rate, blood pressure, cardiac output, stroke volume
b. Hourly urine output and fluid administration
c. A trans-thoracic echocardiogram will be performed prior to and 6hours after study drug administration, where possible.
6. Inotropic variables post dose
a. Hourly measures of vasoactive infusion rates.
7. Biochemical variables post dose
a. Plasma lactate concentrations obtained by arterial blood gas
sampling at 0,3,6 and 12 hours.
b. Renal and liver biochemistry sampling at 0 and 12 hours.
Data analysis
Statistical considerations:
Enrollment will consist of a 20 patient cohort.
Data from Morelli et al (JAMA 2015) demonstrate that the median heart rate in a
similar patient cohort was 114/min at baseline, with a decrease to 85/min
following esmolol infusion. In 2014, ~280 patients were admitted to the Alfred
ICU with a ‘sepsis’ related diagnosis (not specifically requiring vasopressor
infusion). The mean maximum HR was ~100/min on admission, with a standard
deviation of 25/min.
Therefore, with an anticipated mean heart rate of 110 +/- 25/min at baseline,
and a type-1 error of 0.05, a 20 patient cohort provides 80% power to detect an
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absolute reduction in mean heart rate of 15/min following study drug
administration.
Analysis will primarily be conducted using SPSS version 22 (Chicago, IL, USA).
Data will be presented in text and tabulated formats. We will develop a
prospective data analysis plan that will be ratified by the investigators prior to
analysis. This will include (but not be limited to) the following sections:
a. Patient demographics
b. Physiological and biochemical derangements and ICU supports prior
to enrolment
c. Changes in haemodynamics and intensive Care supports following
administration of a single dose of enteric ivabradine
Descriptive statistics will be used to describe overall cases (n) and proportions
(%). Distributed data will be described according to the median and interquartile range (IQR). Inferential statistics will involve the Mann-Whitney U test
for distributed data and the chi-sq / Fischer’s exact test for categorical data.
Data security and handling
All data will be stored in electronic databases on password protected computers.
Governance and oversight
The study will be overseen by investigators with experience in research and
audit. An analysis plan will be agreed on prior to analysis being conducted. All
investigators will contribute to the project. Authorship for peer review
publications will reflect the relative contributions to the study.
Consent:
Written and informed consent will be obtained from the patient or person
responsible. We will not seek procedural authorization where a person
responsible is not available.
Outcomes and significance
Sepsis continues to be a major source of morbidity and mortality. The hallmark
of this syndrome is the development of a systemic inflammatory response,
typically manifest as a low resistance high output circulation. Tachycardia and
arterial hypotension are common clinical signs, and are poorly tolerated by
many patients. Excessive heart rates in particular can predispose to myocardial
ischaemia, stress cardiomyopathy, and impaired diastolic filling. As such,
emerging evidence stresses that acutely controlling heart rate in this context
may lead to significant clinical benefits.
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Ivabradine represents a novel therapeutic option that lowers heart rate, without
impacting on vasomotor tone and cardiac contractility. As such, it represents an
attractive option to treat tachycardia in this setting. To date, there are little data
that have investigated this in a systematic fashion. This project aims to assess the
efficacy of a single enteral dose of ivabradine in tachycardic critically ill septic
patients, while collecting a range of physiological and haemodynamic data to
ensure safety.
Data from this study are likely to inform larger clinical trials with this agent,
which may lead to widespread practice change, and improvements in patient
centred outcomes.
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References
1.
Kaukonen K-M, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic
Inflammatory Response Syndrome Criteria in Defining Severe Sepsis. N
Engl J Med 2015;372(17):1629–38.
2.
Kaukonen K-M, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality Related
to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia
and New Zealand, 2000-2012. JAMA 2014;311(13):1308–16.
3.
Parker MM, Parrillo JE. Myocardial function in septic shock. Journal of
Critical Care 1990;5(1):47–61.
4.
Annane D, Bellissant E, Cavaillon J-M. Septic shock. The Lancet
2005;365(9453):63–78.
5.
Benedict CR, Rose JA. Arterial norepinephrine changes in patients with
septic shock. Circ Shock 1992;38(3):165–72.
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Sander O, Welters ID, Foëx P, Sear JW. Impact of prolonged elevated heart
rate on incidence of major cardiac events in critically ill patients with a
high risk of cardiac complications*. Critical Care Medicine 2005;33(1):81–
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Morelli A, Ertmer C, Westphal M, et al. Effect of Heart Rate Control With
Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic
Shock. JAMA 2013;310(16):1683–9.
8.
Fox K, Komajda M, Ford I, et al. Effect of ivabradine in patients with leftventricular systolic dysfunction: a pooled analysis of individual patient
data from the BEAUTIFUL and SHIFT trials. Eur Heart J
2013;34(29):2263–70.
9.
Shattock M, Camm AJ. Pure heart rate reduction: the I~ f channels from
discovery to therapeutic target. British journal of cardiology 2006;
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De Santis V, Frati G, Greco E, Tritapepe L. Ivabradine: a preliminary
observation for a new terapeutic role in patients with multiple organ
dysfunction syndrome. Clin Res Cardiol 2014;103(10):831–4.
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Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients
with multiple organ dysfunction syndrome by the I f (funny channel
current) inhibitor ivabradine. Clin Res Cardiol 2011;100(10):915–23.
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Ivabradine. MIMS Full Prescribing information; 2014.
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Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in
chronic heart failure (SHIFT): a randomised placebo-controlled study.
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Lancet 2010;376(9744):875–85.
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Borer JS, Böhm M, Ford I, et al. Efficacy and safety of ivabradine in patients
with severe chronic systolic heart failure (from the SHIFT study). Am J
Cardiol 2014;113(3):497–503.
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Fox K, Ford I, Steg PG, Tendera M, Ferrari R, BEAUTIFUL Investigators.
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