Duration of diastole↓
Chronic heart failure
Ventricular efficiency ↓
Elevated heart rate
The role of heart rate in cardiovascular disease
The funny current a inward mixed sodium
potassium current is highly expressed in :
1. SA node
2. AV node
3. Purkinje fibres
These are activated at voltages of diastolic range.
At the end of a sinoatrial action potential the
membrane repolarizes below the If threshold (about
-40/-50 mV), the funny current is activated and
supplies inward current, which is responsible for
starting the diastolic depolarization phase (DD);
Binds the Funny channel
Reduces the slope for
Prolongs diastolic duration
It dose not alter:
1. Ventricular repolarisation
2. Myocardial Contractility
3. Blood Pressure.
B-Blockers may not be tolerated in high
doses to attain heart rate of 70.
In acute settings the negative inotropic
effect could be deleterious.
Advantages over B-Blockers
Protein Binding: 70%
Metabolism: Hepatic ( First- Pass) more than
50% CYP 3A4 mediated
Elimination: Renal and Fecal
Half Life: 2 hours.
Chronic Stable Angina in patients with sinus
rhytm who cannot take B-blocker.
In combination with B-blockers when heart
rate is poorly controlled with b-blockers.
Off-label in treatment of inappropriate sinus
Morbidity-mortality Evaluation of
The If inhibitor Ivabradine in
patients with coronary disease and
left ventricular dysfunction.
To examine the effects of elevated HR (>70 bpm) on
cardiovascular events in these coronary patients
To examine the effects of ivabradine on cardiovascular
events in coronary patients with left ventricular
Heart rate above 70 bpm increases risk of MI by
Prospective data from the BEAUTIFUL placebo arm
Hazard ratio = 1.46 (1.11 – 1.91)
0 0.5 1 1.5 2
Heart rate <70 bpm
Heart rate ≥70 bpm
Ivabradine reduces fatal and nonfatal
myocardial infarction (HR ≥70 bpm)
(HR >70 bpm)
Hazard ratio = 0.64 (0.49 – 0.84)
0 0.5 1 1.5 2
RRR: relative risk reduction
Fox K et al. Lancet. 2008;372:807-816.
Summary of observed cardiovascular risk reduction in
24%0.76Primary composite end point
16%0.84Hospitalization for HF
Predefined end point
Hospitalization for MI
Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery
diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial.
Eur heart Jour On line.
SHIFT (Systolic Heart Failure Treatment
with the If Inhibitor Ivabradine Trial)
In HF in sinus rhythm with HR ≥75 bpm heart rate reduction
with ivabradine improves outcomes, including all-cause
death and cardiovascular death reduces .
Ivabradine-associated risk reductions are related to both
HR achieved and magnitude of HR reduction.
Patients achieving <60 bpm or with >10 bpm reduction
have the best prognosis.
Reduction in the total hospitalizations for worsening HF
Reduction in the incidence of recurrent HF hospitalizations
Increase in time to first and subsequent hospitalizations
Secondary endpoint: change in LVEDVI
from baseline to 8 months
93.9 32.8 85.9 30.9 90.8 33.1 89.0 31.6
-7.9 18.9 -1.8 19.0
Ivabradine (n=204) Placebo (n=199)
Baseline 8 months Baseline 8 months
∆ -5.5, P=0.0019
Left ventricular end-diastolic
Other ongoing trials:
SIGNIFY in patients with coronary artery
disease without heart failure – results are
expected in 2013.
VIVIFY 1st trial assessing safety of
intravenous ivabradine in patients with ST-
segment elevation myocardial infarction.
Clarify : International Registry.
The new ESC guidelines emphasize the goals when
treating patients with established heart failure “to
relieve symptoms and signs (e.g.
oedema), prevent hospital admission, and
Also Resting heart rate is established as a
routine parameter guiding the choice of therapy.
Hence guidelines recommend the addition of
ivabradine in patients with heart failure in sinus
rhythm who have a HR ≥70 bpm and an ejection
fraction ≤35%, and who are already treated with β-
blockers, ACEIs, and MRAs (mineralocorticoid
5mg twice daily and may be increased upto
7.5mg twice daily
Dose may be increased or decreased
according to heart rate
If bradycardia persists then it may be stopped
Luminous Phenomenon (Enhanced
brightness in a fully maintained visual field).
First DegreeAV block,Ventricular extra
Dizziness and/ or blurred vision
Sick Sinus Syndrome
H R <60 prior to treatment
Acute myocardial infarction
Sino atrial block
Unstable or acute heart failure
Concomitantly with inhibitors of CYP3A 4 such as azole
antifungals (ketoconazole), macrolide
antibiotics, nefazodone and the anti-HIV drugs nelfinavir
Take home message
Ivabradine should used in all cases of heart
failure and coronary artery disease rate with
heart rate more than 75.
Effects of renin angiotensin
system on various organs
RENIN AND HYPERTENSION
Overactivity of the RAAS with high renin,
Angiotensin, and aldosterone levels causes
fatal malignant hypertension and renovascular
hypertension, whereas overactivity of the
RAAS with milder elevations of renin levels has
been associated with up to 70% of cases of
Inhibition of Ang II formation or action via ACEIs or
ARBs leads to compensatory increase in renin .
Ang II can also be formed using pathways that do not
Circulating renin can be taken up by cardiac and
coronary tissues, leading to the long-lasting
generation of Ang II via ACE and non-ACE activity
that is only partially suppressed by an ACEI.
Therefore Inhibition of renin would favor more
complete blockade of the system.
Direct Renin Inhibitors
Aliskiren is the first of these new nonpeptide
DRIs to be approved by the FDA for the
treatment of hypertension. It is administered
once daily per orally, either as monotherapy or
in combination with other antihyper- tensive
agents also in Europe, aliskiren received
approval for the treatment of hypertension.
Aliskiren is a highly potent inhibitor of renin
with a high affinity for renin and a high
species specificity for primate renin.
It binds to S3bp binding site of renin essential
for its activity.
Binding to this pocket prevents the
conversion of angiotensinogen to
Peak plasma concentration – 1- 2 hrs
Steady state after –5-8 days .
Pathway of elimination:-
1. Mainly via biliary excretion as unmetabolised
2. Less than 1% of an orally administered dose is
excreted in urine.
Aliskiren is not metabolized by, and does not
induce or inhibit, cytochrome P450 enzymes and
shows no clinically relevant pharmaco- kinetic
150 mg once daily
May increse upto 300mg if B P is not
controlled after two weeks .
Dose more than 300 did not provide
additional blood pressure control rather
INDICATIONS AND USAGE
•Aliskiren is indicated for the treatment of
• Lowering blood pressure reduces the risk of
fatal and nonfatal cardiovascular
events, primarily strokes and myocardial
•There are no controlled trials
demonstrating risk reduction with Aliskiren.
Pregnancy: Category D
Reduces fetal renal function and increases fetal
and neonatal morbidity and death.
Resulting oligohydramnios can be associated
with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects
include skull hypoplasia, anuria,hypotension,
renal failure, and death.
When pregnancy is detected, discontinue it as
soon as possible
2)Diabetic receiving ARBs or ACEIs
Because of the increased risk of
3) Anaphylactic Reactions and Head
and Neck Angioedema
Hypersensitivity reactions such as
anaphylactic reactions and angioedema of
the face, extremities, lips, tongue, glottis.
DiscontinueAliskiren immediately in patients
who develop anaphylactic reactions or
angioedema, and do not readminister.
In patients with an activated renin-angiotensin
system, such as volume- and/or salt-depleted
patients symptomatic hypotension may occur
after initiation of treatment with Aliskiren.
This condition should be corrected prior to
administration of Aliskiren, or the treatment
should start under close medical supervision.
A transient hypotensive response is not a
contraindication to further treatment, which
usually can be continued without difficulty once
the blood pressure has stabilized.
5) Impaired Renal Function
Monitor renal function periodically in patients
treated with Aliskiren whose renal function
may depend in part on the activity of the renin-
angiotensin system (e.g., patients with renal
artery stenosis, severe heart
failure, postmyocardial infarction or volume
depletion) or patients receiving ARB,ACEI or
non-steroidal anti-inflammatory (NSAID).
Risk factors for the development of
hyperkalemia include renal
insufficiency, diabetes, combination use with
ARBs or ACEIs NSAIDs, or potassium
supplements or potassium sparing diuretics.
7) Cyclosporine or Itraconazole
When aliskiren was given with cyclosporine or
itraconazole, the blood concentrations of
aliskiren were significantly increased. Avoid
concomitant use of aliskiren with cyclosporine or
Hyerkalemia ( Particularly when used with ACE
inhibitors in diabetic patients)
Hypotension (Particularly in volume depleted
Diarrhoea and other GI symptoms.
Elevated uric acid, gout and renal stones.
Limited data are available related to
overdosage in humans.The most likely
manifestation of overdosage would be
hypotension. If symptomatic hypotension
occurs, supportive treatment should be
Aliskiren is poorly dialyzed.Therefore,
hemodialysis is not adequate to treat
aliskiren overexposure .
The antihypertensive effects of Aliskiren have
been demonstrated in six randomized, double-
blind, placebo-controlled 8-week clinical trials in
patients with mild-to-moderate hypertension.
A substantial proportion (85%-90%) of the blood
pressure lowering effect was observed within 2
weeks of treatment .With cessationof
treatment, blood pressure gradually returned
toward baseline levels over a period of several
There was no evidence of rebound hypertension
after abrupt cessation of therapy.
With Hydrochlorthiazide : Additive
With Amlodipine: Additive
Aliskiren in Patients with
Diabetes treated with ARB or
ACEI (ALTITUDE study)
Patients with diabetes with renal disease
(defined either by the presence of albuminuria or
reduced GFR) were randomized to aliskiren 300
mg daily and placebo . All patients were
receiving background therapy with an ARB or
ACEI.Trial was halted due to increased incidence
of nonfatal stroke, renal complications,
Hyperkalemia and hypotension in patients with
diabetes and renal impairment.
Relating to cardiac diseases
ALLAY and ASPIRE trials show that
there is no positive impact on LV
hypertrophy or LV remodeling with
1. Aliskiren and ARB or
2. Aliskiren and ACE inhibitor therapy.
Addition of Aliskiren in heart failure patients
shows reduction of neurohumoral activation
–(BNP and NT-pro-BNP which were
previously linked to adverse outcome in
patients with heart failure) .
These data are encouraging but not
Results of two trials ATMOSPHERE and
ASTRONAUT regarding its beneficial role in
heart failure patients are underway.
Finally the Aliskiren in Prevention of Later
Life Outcomes (APOLLO) trial will address
elderly patients with a systolic BP 130 to 159
mm Hg, no overt cardiovascular disease, and
a high cardiovascular risk profile, in order to
test the efficacy of the drug in reducing the
risk of major cardiovascular end points.
Take Home Message
1. Can be used as alternative to various
antihypertensive as monotherapy or as
combination therapy .
2. Regarding beneficial role in cardiovascular
diseases and renal diseases ?