Transcript Introduction of current development and concept

Introduction of current
development and concept
cardiovascular physiology and
pharmacology
Mohammad Saifur Rohman,
MD. PhD. FIHA
Lab. Cardiology and Vascular Medicine
Faculty of Medical, Brawijaya University
Outline
• Physiology of CV
• Pathogenesis of CV
• Current development and concepts of CV
drugs
Blood Flow Through Heart
Blood Flow Through and Pump Action of
the Heart
Coronary Arteries
• Originates from the aorta
just beyond the aortic
valve
• Coronary blood flow to
the myocardium occurs
primarily during diastole
* To maintain adequate
blood flow through the
coronaries, mean arterial
pressure (MAP) must be
at least 60 mmHg
Intrinsic Cardiac Conduction System
Approximately 1% of cardiac muscle cells are autorhythmic rather than contractile
70-80/min
40-60/min
20-40/min
Type of Cells in The Heart
• Pacemaker cells
• – 5 – 10 um in length;
• Sinoatrial and atrioventricular nodes
• – Spontaneous depolarization
• – Action Potential
• Electrical conducting cells
• – Long thin cells
• Atrial conducting system
• Ventricular conducting system
• Myocardial cells
• – Contractile units in the heart, most are myocardial cells
• – Calcium is responsible for contractile process after
initiation of action potential
Physiology of the Heart
• Electrophysiologic properties (regulates heart rate &
rhythm)
- Automaticity – ability of all cardiac cells to initiate an
impulse spontaneously & repetitively
- Excitability – ability of cardiac cells to respond to
stimulus by initiating an impulse (depolarization)
- Conductivity – cardiac cells transmit the electrical
impulses they receive
- Contractility – cardiac cells contract in response to an
impulse
- Refractoriness – cardiac cells are unable to respond to
a stimulus until they’ve recovered (repolarized)
Ion movement and channels
• The movement of specific ions across the cell
membrane serve as action potentials depends on :
• 1. Energetic favorability; concentration gradient and
transmembrane potential
• 2. Permeability of the membrane for the ion: channels
which is selective and gated
• Selective: manifestation of size and structure of its
pore
• Gated: pass through it specific channels only at certain
times; voltage sensitive gating (fast sodium channel)
Action potential in autorhythmic cells
Action Potential in contractile cells
Different pattern of Membrane potential
at different cells
Action Potential in contractile cells and ECG
Heart Excitation Related to ECG
P wave: atrial
depolarization
START
P
The end
R
PQ or PR segment:
conduction through
AV node and A-V
bundle
T
P
P
QS
Atria contract.
T wave:
ventricular
Repolarization
Repolarization
R
T
P
ELECTRICAL
EVENTS
OF THE
CARDIAC CYCLE
QS
P
Q wave
Q
ST segment
R
R wave
R
P
QS
P
R
Ventricles contract.
Q
P
S wave
QS
Cardiac Cycle - Filling of Heart Chambers
• Heart is two pumps that work together, right and left half
• Repetitive contraction (systole) and relaxation (diastole) of
heart chambers
• Blood moves through circulatory system from areas of higher
to lower pressure.
– Contraction of heart produces the pressure
Cardiac Cycle - Mechanical Events
1
START
5
4
Isovolumic ventricular
relaxation: as ventricles
relax, pressure in ventricles
falls, blood flows back into
cups of semilunar valves
and snaps them closed.
Ventricular ejection:
as ventricular pressure
rises and exceeds
pressure in the arteries,
the semilunar valves
open and blood is
ejected.
Late diastole: both sets of
chambers are relaxed and
ventricles fill passively.
Atrial systole: atrial contraction
forces a small amount of
additional blood into ventricles.
2
3
Isovolumic ventricular
contraction: first phase of
ventricular contraction pushes
AV valves closed but does not
create enough pressure to open
semilunar valves.
Figure 14-25: Mechanical events of the cardiac cycle
Wiggers Diagram
0
100
200
Time (msec)
300
400
QRS
complex
Electrocardiogram
(ECG)
P
500
600
700
800
QRS
complex
Cardiac cycle
T
P
120
90
Dicrotic
notch
Pressure
(mm Hg)
Left
ventricular
pressure
60
30
Left atrial
pressure
S1
Heart
sounds
S2
EDV
135
Left
ventricular
volume
(mL)
Atrial systole
ESV
65
Atrial
systole
Isovolumic
ventricular
contraction
Ventricular
systole
Ventricular
systole
Ventricular
diastole
Early
ventricular
diastole
Atrial
systole
Late
ventricular
diastole
Atrial
systole
Modulation of Cardiac Contractions
Regulation of Cardiac Output
Figure 18.23
Normal Endothelial Function
Endothelial Dysfunction :
Atherogenesis
Atorvastatin calcium Extensively Studied in Large Trials
Atorvastatin effectively reduces LDL-C Across a Broad Range of Patients
10 mg
10,305 patients
without CHD
in ASCOT-LLA
LDL-C level at
randomisation
Follow-up
LDL-C level
Outcomes
133
mg/dL
90
mg/dL
• 36% RRR
of nonfatal MI
and fatal CHD
• 27% RRR
of stroke
80 mg*
2838 patients
10,001 patients
654 patients
4162 patients
in CARDS
in TNT
in REVERSAL
in PROVE IT
<130
mg/dL
150
mg/dL
106
mg/dL
with diabetes
116
mg/dL
77
mg/dL
• 37% RRR
of death and
major CV
events
• 48% RR
of stroke
with CHD
77
mg/dL
• 22% RR of
major CV
events
• 25% RR
of stroke
with CHD
with CHD
79
mg/dL
62
mg/dL
Significantly
impacted
atherosclerotic
disease
progression;
pravastatin
was associated
with further
disease
progression
• 16% RR of
major CV events
versus
pravastatin
*80 mg is not
a starting dose.
RR=risk reduction.
Nissen et al. JAMA. 2004;291:1071-1080; Cannon et al. N Engl J Med. 2004;350:1495-1504; LaRosa et al. N Engl J Med. 2005;352:1425-1435;
Sever et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158; Colhoun et al. Lancet. 2004;364:685-696.
Atherosclerosis  ACS
STEACS vs. NSTACS
Occluded artery
ECG featured of Ischemic cell
Arrhythmias Detected on ECG continued
• In third-degree or complete AV node block, no atrial activity
passes to ventricles
– Ventricles are driven slowly by bundle of His or Purkinjes
Therapeutic Options in Acute
Coronary Syndromes
•
•
•
•
•
Anti-ischemic treatment
Antiplatelet agents
Anticoagulants
Revascularization/Reperfusion/Thrombolysis
Long term treatment/secondary prevention
Targets for anti thrombotics
Tissue factor
Collagen
Aspirin
Plasma clotting
ADP
cascade
Thromboxane A2
Direct Xa inhib
LMWH
Heparin
Prothrombin
AT
Factor
Xa
Bivalirudin
Hirudin
Dabigatran
Clopidogrel
Prasugrel
AZD 6140
Conformational
activation of GPIIb/IIIa
Thrombin
Fibrinogen
GPIIb/IIIa
inhibitors
Platelet aggregation
Fibrin
Thrombus
NSTE-ACS : Antiplatelets
What, when and How?
What?
Invasive 1,2
Conservative 2
Aspirin
Ticagrelor* / Clopidogrel‡
Aspirin
Ticagrelor* / Clopidogrel‡
When ?
How ?
Loading dose ASAP
Aspirin: started at a dose of 150–300 mg and at a
maintenance dose of 75–100 mg, plus
Ticagrelor: 180 mg LD, 90 mg twice daily, or
Clopidogrel: 300 or 600 mg LD, 75 mg daily
Upstream GPIIbIIIa are not recommended in patients
with high ischaemic risk
‡All patient received clopidogrel LD before PCI in CURRENT
* Ticagrelor has limited experience for prePCI loading
1. Wijns W et al Eur Heart J 2010;31:2501-55
2. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr236
3. Anderson JL et al Circulation 2007;116:148-304
Aspirin: started at 150–300 mg and at a
maintenance dose of 75–100 mg, plus
Ticagrelor 180 mg LD, 90 mg twice daily, or
Clopidogrel: an immediate 300 mg LD, 75 mg daily
dose
ST-ACS: Oral antiplatelet
What, when and how ?
What ?
Primary PCI1
Thrombolysis2
Aspirin
Clopidogrel / Prasugrel* / Ticagrelor*
Aspirin
Clopidogrel
When ?
How?
ASAP
Aspirin: mulai 150–300mg per oral or 250–500mg bolus
iv dilanjutkan dengan 75-100mg/hari
Prasugrel: 60mg Loading dilanjutkan 10mg /hari atau
Ticagrelor: 180mg Loading dilanjutkan 2x90mg/ hari atau
Clopidogrel: 600mg Loadingdilanjutkan 75mg /hari
1. Wijns W et al Eur Heart J 2010;31:2501-55
2. Van de Werf F et al Eur Heart J 2008;29:2909-45
Aspirin: 150-325mg per oral or i.v. 250mg iika tidak
mungkin per oral.
Clopidogrel: loading 300mg jika usia ≤75 tahun; 75mg
jika usia >75 tahun
ESC Guidelines
Doses of antiplatelet and
antithrombin co-therapies
ESC Guidelines for the management of AMI in patients presenting with ST-segment elevation, 2012
Contractile Dysfunction in IHD
Myocardial ischaemia
Oxygen Supply and Demand Are Mismatched During
Leading to Impaired Diastolic Relaxation
Vasospasm
X
Thrombus
Atherosclerosis
Diltiazem, Amlodipine,
Nicorandil, Nitrates
β-Blockers,
Verapamil/Diltiazem,
Ivabradine
Microvascular
Flow
O2
Supply
Ischaemia
,
Afterload
X
Heart
X rate
Contractility
X
Preload
O2
Demand
β-Blockers,
Verapamil/Diltiazem
Ischaemia
β-Blockers, Calcium Antagoni
- Induced
Sodium
Calcium Overload
Relaxation
Impaired Diastolic
Adapted from Chaitman BR. Circulation 2006;113:2462
-72.
Adapted from Belardinelli L et al. Eur Heart J 2004;6(Suppl I):I3
-7.
Diastolic Wall
Tension
New Approach of Ischemic Heart Disease
Traditionally, ischemic heart disease is treated by
pharmacological or mechanical means that act primarily
either to increase oxygen supply to the heart or to decrease
oxygen demand of the heart muscle
Recently, an additional approach to treating ischemic heart
disease is by means of metabolic modulation, whereby
optimizing energetics in the myocardium can improve cardiac
efficiency of the heart muscle
1. Ussher JR. et al. Basic Res Cardiol. 2009;104:203–10.
2. Stanley WC et al. Physiol Rev. 2005;85:1093–129.
3. Lam A et al. Curr Opin Pharmacol. 2007;7:179–85.
New mechanistic approaches to chronic
stable angina
Rho kinase inhibition (fasudil)
Metabolic modulation (trimetazidine)
N
SO2
N
CH3
CH3
NH
O
N
O
H
O CH3
N
CH3
N
O CH3
H
N
O
CH3
H
O NO2
N
O
Late INa inhibition (ranolazine)
CH3
H
Preconditioning (nicorandil)
H3 C O
H3 C O
O
N
Sinus node inhibition (ivabradine)
N
CH3
O
OH
N
N
OCH3
O
NEW CONCEPT IN CARDIAC METABOLISM
 Former concept (in past decades):
 Chronic heart failure associated with chronic coronary
artery disease (CAD) is irreversible
 It should be treated with hemodynamic agents
 New concept (progress in cardiac imaging techniques):
 CHF associated with chronic CAD is reversible
 Cause of reversible left ventricle dysfunction is
Hibernation and Stunning
 It highlights the impact of metabolic changes
Energy Utilization in Ischemia
Classification of Blood Pressure
ESC-ESH 2007
JNC-VII
Optimal
: <120 and < 80
Normal
: 120-129 and/or 80 - 84
High Normal : 130-139 and/or 85-89
Grade 1 : 140-159 and/or 90-99
Grade 2 : 160-179 and/or 100-109
Grade 3 : > 180 and/or > 110
Normal
Pre-hypertension
Stage 1
Stage 2
H
Y
P
E
R
T
E
N
S
I
O
N
JNC VII committee, JAMA 2003: 289;2560-2572
History of Hypertension Management
• Hypertension: entered the language of
medicine in the 19th and early 20th centuries.
• The history of hypertension can be divided
into two eras:
1. Pre-treatment Era (before 1967)
2. Treatment era (established the benefit of
drug therapy for hypertension)
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Pretreatment
 During the first 120 years of hypertension
research (from the 1840s to 1965) basic and
clinical research defined the following (1):
1. The mechanisms of increased BP
2. The natural history of untreated HTN to CVD
3. Causes of secondary HTN
4. Set the stage for recognizing potential therapy
through drug treatment
 Non farmacological treatments: Phlebotomy,
purgatives Loss of Water and sodium (2)
1. Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
2. Hoobler SW. Hoeber-Harper Book, N York 1959
Diet for HTN
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Surgical (Sympathectomy) for HTN
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Farmacotherapy for HTN
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Regulation of BP
Excess sodium
intake
Renal
Sodium
retention
Reduced
Nephron number
Stress
Decreased Sympathetic
Filtration nervous
overactivity
surface
Fluid Volume
Preload
Venous
Constriction
Contractility
Genetic
Alteration
Endothelium
derived factors
Renin
Angiotensin
Excess
Hyperinsulinemia
Cell membrane
alteration
Functional Constriction
Structural Hypertrophy
Blood Pressure = Cardiac Output (CO) X Peripheral Resistance (PR)
Hypertension
Increased CO
and/or
Increased PR
Autoregulation
Kaplan NM, Clinical Hypertension 7th ed. 2002; 63
Obesity
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
LIFESTYLE MODIFICATIONS
Not Goal BP
INITIAL DRUG CHOICES
Without Compelling Indications
Stage 1
Stage 2
Thiazide-Type
diuretics for most.
May consider ACEI,
ARB, BB, CCB, or
combination
Two –Drug
combination for most
(usually thiazide-type
diuretic and ACEI, or
ARB, or BB, or CCB
With Compelling Indications
Drug(s) for the compelling
indications.
Other antiHT Drugs
(Diuretics, ACEI, ARB, ,
CCB) as needed
US-JNC VII Report
Clinical Trial and Guideline Basis for
Compelling Indications (JNC VII 2003)
Aldo Ant
CCB
ARB
ACEI
BB
Compelling Indication*
Diuretic
Recommended Drugs
Clinical trial basis
Heart Failure
ACC/AHA Heart Failure Guideline, MERITHF,
COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT,
RALES, CHARM
Postmyocardial Infarction
ACC/AHA Post-MI Guideline, BHAT, SAVE,
Capricorn, EPHESUS
High Coronary Disease Risk
ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA,
INVEST
Diabetes
NKF-ADA Guideline, UKPDS, ALLHAT
Chronic Kidney Disease
NKF Guideline, Captopril Trial, RENAAL, IDNT,
REIN, AASK
Recurrent Stroke Prevention
PROGRESS
Amlodipine besylate Extensively Studied in
Large Trials
ALLHAT
ASCOT-BPLA
VALUE
CAMELOT/
NORMALISE
Patients
studied
High-risk
hypertensive
(N=33,357)
High-risk
hypertensive
(N=15,245)
CHD
patients
(n=1991)
Comparators
Amlodipine
besylate,
lisinopril,
chlorthalidone
Amlodipine
besylate,
valsartan
Amlodipine
besylate,
enalapril,
placebo
Trial duration
6 years
Moderate-risk
hypertensive
(N=19,342)
Amlodipine
besylate
perindopril,
atenolol
thiazide
Trial
stopped
early
6 years
2 years
End point:
cardiac morbidity
and mortality
End point: CV events
and plaque progression
End points: CHD death
and nonfatal MI
ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997; Julius et al, for the VALUE trial group. Lancet.
2004;363:2022-2031; Sever et al, for the ASCOT Investigators.
J Hypertens. 2001;19:1139-1147; Nissen et al, for the CAMELOT Investigators. JAMA. 2004;292:2217-2226.
Emerging Role of Gene in HTN
Gene Polymorphism :
• Aldosteron synthase
• Angiotensin
• Epithelial sodium transport (Liddle’s
syndrome)
• Amiloride sensitive sodium channel
• WNK kinase system
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Single
Nucleotide
Polymorphism
Consequence of Gene Polymorphism
• Gene polymorphism
A large, prospective study published on July
2009 in JACC : Differences in beta-blocker
effectiveness and variability in beta-blocker
responses among African Americans
attributed to polymorphisms that affect
beta receptors
• Pharmacogenomic
• Different response to drug may be correspond
to ethnic/race and familial
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Different Combination of Treatment ?
• Race base therapy, raise from a difference
response of HTN treatment between white and
black
• Indonesian are White or Black?
• Specific race researches are warranted to
achieve blood pressure target worldwide.
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
Respond to the same antihypertensive drug ?
The Progression from Hypertension
to Heart Failure
LVH
Diastolic
dysfunction
CHF
Hypertension
Systolic
dysfunction
MI
LV
Normal LV
Structure & Function remodeling
Time
(decades)
Death
Subclinical
Overt
LV dysfunction Heart Failure
Time
(months)
Vasan RS, Levy D. 1996. Arch Intern Med 156 : 1759-1796
The Cardiovascular Continuum
Coronary
thrombosis
Myocardial
infarction
Myocardial
ischaemia
CAD
Atherosclerosis
LVH
Risk factors
Hypertension, smoking, cholesterol, diabetes
Sudden Death
Arrhythmia &
loss of muscle
Remodelling
Ventricular
dilatation
Congestive
heart failure
Death
Dzau V. Braunwald E, Am Heart J. 1991
THE DONKEY ANALOGY
Ventricular dysfunction limits a patient's ability to perform the
routine activities of daily living…
HEART FAILURE
ERAS OF HEART FAILURE MANAGEMENT
Non-pharmacological
• Bed rest
Pharmacological
• Gene therapies
• Digitalis
• Inactivity
• Fluid restriction
• (Digitalis, diuretics)
pre -1980’s
Cellular/genetic
1980’s
• Diuretics
• Cell implantation/
regeneration
• Neurohormonal interventions
• Xenotransplantation
1990’s
2000’s
2020’s ⇒
Pharmacological
Device
• Digitalis
• CRT
• Diuretics
• ICDs
• Vasodilators
• LVADs
• Inotropes
• Others?
Heart Failure Updates, 2003
TREATMENT OPTION FOR HF
INOTROPIC
Like the carrot placed in front of the donkey
ACEI AND DIURETICS
Reduce the number of sacks on the wagon
Nowtreatment previously
Preferred
Heart Failure
Myocardial Infarction
ACE-I
B Blocker
ß-BLOKERS
Limit the donkey’s speed, thus saving energy
ACTIVATION OF NEUROHORMONAL
PATHWAYS IN HF
Coronary Disease
Cardiomyopathy
Cardiac Overload
Left Ventricular Dysfunction
Vasoconstriction
Neurohormonal Activation
• Cathecholamines
• RAAS
• AVP
• Endothelin
 Peripheral organ
blood flow
Cardiac remodelling
 Skeletal
muscle flow
Exercise intolerance
Na+
 RBF
retention
Edema, congestion
LV dilatation
Sudden death
LV
hypertrophy
Pump failure
Ruffolo, J.Cardiovasc Pharmacol,1998
Renin-Angiotensin-System Blockers
Liver
Kidney
Angiotensinogen
X
Renin
Bradykinin
ACE inhibitors
X
Angiotensin I
X
ACE
Inactive kinins
Direct Renin Inhibitor
Angiotensin II
X
Retention of salt
and water
Vasoconstriction
Blood pressure increases
Kaplan NM, Clinical Hypertension 7th ed. 2002; 63
ACE inhibitors (ACEi)
Angiotensin II
Receptor Blokers (ARB)
Inhibition of the RAAS by ACE inhibitors
Angiotensinogen
(-)
ACE
inhibitor
Renin
Bradykinin
Angiotensin I
Nonrenin
Angiotensinconverting
enzyme
NonACE
Inactive kinins
Angiotensin II
ARB
BP
AT1
• Vasoconstriction
• Aldosterone secretion
• Catecholamine release
• Proliferation
• Hypertrophy
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;
Carey RM, et al. Hypertension 2000;35:155-163
AT2
•
•
•
•
•
Vasodilation
Inhibition of cell growth
Cell differentiation
Injury response
Apoptosis
ACEI Reduced Mortality and Morbidity
Trials
Mortality
Reduction
Sample Size
Follow up
SAVE
2.231 AMI
24-60
months
SOLVD
4.228 without,
2568 with overt
HF
> 3 years
8-16 %
AIRE
2.006 AMI with HF
15 months
18-30%
TRACE
1.h749 AMI with LV
dysfunction
24-50 months
ATLAS
3.164 CHF
39-58 months
GISSI3
18.895 AMI
6 weeks
Morbidity Reduction
19-32%
Recurent MI 25%
Overt HF 29%,
Remodeling
Prevented
progression to
severe heart
7.60%
failure
8% Hospitalization 16-14%
6.70%
Whats what 2006
ADRENERGIC ACTIVATION
IN MYOCARDIAL DYSFUNCTION
Myocardial Insult
Myocardial Dysfunction
Increased Load
Reduced Systemic Perfusion
Cardiac Adrenergic Activation
Altered Gene
Expression
Growth and
Remodeling
Toxicity, Ischemia,
or Energy Depletion
Necrosis
Apoptosis
Cell Death
Bristow MR. Am J Cardiol 1997;80(11A):26L-40L
1.0
100
CIBIS-II
COPERNICUS
90
Survival (%)
Placebo
Risk reduction = 34%
80
Carvedilol
(n=1156)
70
Placebo
(n=1133)
35% risk reduction
p < 0.0001
p  0.001
0.6
60
0
0
0
200
400
600
0
800
Days after inclusion
3
CIBIS-II Investigators
(1999)
Placebo
Metoprolol CR/XL
Cumulative mortality (%)
6
9
12
15
Months of follow up
20
15
MERIT-HF
10
5
Risk reduction = 34%
p = 0.0062
0
0
3
6
9
12
Follow up (months)
16
18
21
MERIT-HF Study Group.(1999)
Survival
Bisoprolol
0.8
18
21
Packer et al. 2001
-Blockers in Heart Failure
All-Cause Mortality
-BLOCKER THERAPY ON SURVIVAL
IN CHF
NYHA II
CIBIS II
MERIT-HF
US Carvedilol program
NYHA III
NYHA IV
Ischemic
Level of Evidence A
Non ischemic
0
0.5
1
Relative Risk
1.5
95% CI
2
Compliance at 1 year with antihypertensive
treatment
Compliance at 1 year (%)
70
60
64 *
* p<0.007 vs ACE inhibitors
58
50
50
40
43
38
30
20
10
0
Diuretics
Beta-blockers
CCBs
ACE, angiotensin-converting enzyme;
CCB, calcium-channel blocker; ARB, angiotensin II receptor blocker
ACE inhibitors
ARBs
Bloom BS, et al. Clin Ther 1998;20:671-681
IC50 (nM)
Olmesartan has greater binding affinity for
the AT1 receptor than losartan
100
90
80
70
60
50
40
30
20
10
0
92
16
8
Olmesartan
Losartan
EXP3174
12
Candesartan
Koike H, et al. J Hypertens 2001;19(suppl 1):S3-S14
IC50: the lower the IC50, the greater the binding affinity
These results were found in a rat study and may not be reflected in humans
Change from predose to 24 hours
in mean PRA (ng/mL/h)
Olmesartan may give more prolonged AT1
blockade than irbesartan or valsartan
5
p vs placebo
4
<0.0001
p vs olmesartan
0.005
0.058 (NS)
0.004
0.028
0.002
0.036
3.16
n=20
3
1.84
1.78
2
1.19
1
0
0
Placebo
Olmesartan Irbesartan
40 mg
300 mg
PRA, plasma renin activity
Performed in healthy volunteers in 1-dose study;
PRA response may not predict those in hypertensive patients
Valsartan
160 mg
Valsartan
320 mg
Jones M, et al. Presented at ASH 2006; Abstract P-195
Lower pill burden: better adherence
As the number of pre-existing Rx meds increased, the likelihood
of adequately refilling AHT and LLT decreased
Likelihood of achieving adherence
Number of
pre-existing
Rx medications
0.0
0.5
1.0
1.5
2.0
2.5
Adjusted odds ratio for
adherence to both AHT
and LLT*
(PDC ≥80%) (95%
confidence interval)
1.00 (reference group)
≥6
3-5
1.23 (1.10-1.38)
2
1.30 (1.14-1.49)
1
1.61 (1.40-1.84)
0
1.96 (1.72-2.25)
Lesser
Greater
*P<0.001 for all groups versus reference group.
Retrospective cohort study of a managed care population. N=8406 patients with hypertension who added AHT and LLT to existing Rx meds within a 90-day period. Adherence
to concomitant therapy: sufficient AHT and LLT Rx meds to cover ≥80% of days per 91-day period.
Chapman RH, et al. Arch Intern Med. 2005;165:1147-1152.
Fixed Dose Combination
Patients fully compliant (%)
Cohort study of
general practice research data (N=755)
100
Fixed-dose combination therapy
80
Co-administration of two pills
60
40
20
0
17%
21%
0
3
6
9
12
15
18
21
24
27
Months since start of therapy
Patients on free combination had a higher odds ratio (OR) of being
non-compliant than patients on FDC: OR 2.09 (95% CI: 1.69, 2.59)
Summary
• Rapid acceleration of current concepts and
drug development in CV = Molecular
Cardiovascular research
• 1 drug = certain target (pleotropic effect)
• Complex disease= multi drug=poly pill
• Fixed dose combination technology
• 3x1x, Pharmacokinetic/ Pharmacodynamic