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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 - PowerPoint PPT Presentation
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Introduction of current development and concept
cardiovascular physiology and pharmacology
Mohammad Saifur Rohman,MD. PhD. FIHA
Lab. Cardiology and Vascular MedicineFaculty 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 SystemApproximately 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: atrialdepolarizationSTART
Atria contract.
PQ or PR segment:conduction throughAV node and A-Vbundle
P
P
Q
Q wave
R wave
P
Q
R
S wave
QS
R
P
ELECTRICALEVENTSOF THE
CARDIAC CYCLE
Repolarization
ST segment
Ventricles contract.
P
Q
R
S
The end
T wave:ventricular
Repolarization
P
QS
R
T
P
QS
R
T
P
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
Figure 14-25: Mechanical events of the cardiac cycle
START
Late diastole: both sets ofchambers are relaxed andventricles fill passively.
Atrial systole: atrial contraction forces a small amount of additional blood into ventricles.
Isovolumic ventricular contraction: first phase of ventricular contraction pushes AV valves closed but does not create enough pressure to open semilunar valves.
Isovolumic ventricularrelaxation: 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.
5
4
1
2
3
Wiggers DiagramElectro-
cardiogram(ECG)
Pressure(mm Hg)
Heartsounds
Leftventricular
volume(mL)
Dicroticnotch
PCardiac cycle
Atrialsystole
Atrialsystole
Ventricularsystole
Ventriculardiastole
PT
S2S1
Atrial systole Ventricularsystole
Early ventricular
diastole
Late ventricular
diastole
Atrialsystole
Isovolumicventricular contraction
Leftventricular
pressureLeft atrialpressure
65
135
30
60
90
120
Time (msec)0 100 200 300 400 500 600 700 800
Aorta
QRScomplex
QRScomplex
EDV
ESV
Modulation of Cardiac Contractions
Regulation of Cardiac Output
Figure 18.23
Normal Endothelial Function
Endothelial Dysfunction :
Atherogenesis
Atorvastatin calcium Extensively Studied in Large TrialsAtorvastatin effectively reduces LDL-C Across a Broad Range of Patients
*80 mg is nota 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.
LDL-C level at randomisation
90mg/dL
10,305 patientswithout CHDin ASCOT-LLA
133mg/dL
2838 patientswith diabetes
in CARDS
77mg/dL
116mg/dL
Follow-upLDL-C level
10,001 patientswith CHD
in TNT
77mg/dL
<130mg/dL
654 patientswith CHD
in REVERSAL
79mg/dL
150mg/dL
4162 patientswith CHDin PROVE IT
62mg/dL
106mg/dL
10 mg 80 mg*
• 36% RRRof nonfatal MIand fatal CHD• 27% RRR
of stroke
• 37% RRR of death and
major CV events
• 48% RRof stroke
Outcomes • 22% RR of major CV
events• 25% RR
of stroke
Significantly impacted
atherosclerotic disease
progression; pravastatin
was associated with further
disease progression
• 16% RR ofmajor CV events
versuspravastatin
Atherosclerosis ACS
STEACS vs. NSTACS
Occluded artery
ECG featured of Ischemic cell
• In third-degree or complete AV node block, no atrial activity passes to ventricles– Ventricles are driven slowly by bundle of His or Purkinjes
Arrhythmias Detected on ECG continued
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
Plasma clottingcascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Collagen
Thromboxane A2
ADP
AT
Aspirin
ClopidogrelPrasugrelAZD 6140
GPIIb/IIIainhibitors
BivalirudinHirudin
Dabigatran
FactorXa
LMWHHeparin
Direct Xa inhib
Invasive 1,2 Conservative 2
What?
When ?
How ?
AspirinTicagrelor* / Clopidogrel‡
AspirinTicagrelor* / Clopidogrel‡
Loading dose ASAP
Aspirin: started at a dose of 150–300 mg and at a maintenance dose of 75–100 mg, plusTicagrelor: 180 mg LD, 90 mg twice daily, orClopidogrel: 300 or 600 mg LD, 75 mg daily Upstream GPIIbIIIa are not recommended in patients with high ischaemic risk
Aspirin: started at 150–300 mg and at a maintenance dose of 75–100 mg, plusTicagrelor 180 mg LD, 90 mg twice daily, orClopidogrel: an immediate 300 mg LD, 75 mg daily dose
1. Wijns W et al Eur Heart J 2010;31:2501-552. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr2363. Anderson JL et al Circulation 2007;116:148-304
‡All patient received clopidogrel LD before PCI in CURRENT* Ticagrelor has limited experience for prePCI loading
NSTE-ACS : AntiplateletsWhat, when and How?
ST-ACS: Oral antiplateletWhat, when and how ?
What ?
When ?
How?
AspirinClopidogrel / Prasugrel* / Ticagrelor*
AspirinClopidogrel
ASAP
Aspirin: mulai 150–300mg per oral or 250–500mg bolus iv dilanjutkan dengan 75-100mg/hariPrasugrel: 60mg Loading dilanjutkan 10mg /hari atauTicagrelor: 180mg Loading dilanjutkan 2x90mg/ hari atauClopidogrel: 600mg Loadingdilanjutkan 75mg /hari
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
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
Primary PCI1 Thrombolysis2
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 ischaemiaOxygen Supply and Demand Are Mismatched During Ischaemia, Leading to Impaired Diastolic Relaxation
Adapted from Chaitman BR. Circulation 2006;113:2462 -72.Adapted from Belardinelli L et al. Eur Heart J 2004;6(Suppl I):I3 -7.
VasospasmThrombus
Atherosclerosis
AfterloadHeart rateContractilityPreload
O2SupplyO2Demand
Ischaemia
MicrovascularFlow
Sodium- InducedCalcium Overload
Diastolic WallTension
Impaired DiastolicRelaxation
Diltiazem, Amlodipine, Nicorandil, Nitrates
X
β-Blockers, Verapamil/Diltiazem
XX
β-Blockers, Calcium Antagonists
X
β-Blockers, Verapamil/Diltiazem, Ivabradine
New Approach of Ischemic Heart Disease
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.
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
New mechanistic approaches to chronic stable angina
Sinus node inhibition (ivabradine)
Late INa inhibition (ranolazine)
Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine)
Preconditioning (nicorandil)O
H3C O
H3C ON
CH3
O CH3
O CH3
NO
N
CH3
H
CH3
CH3 O
O H
N
SO2 NHN
O
O NO2H
N
O
OHCH3
CH3
OCH3HN N N O
N
N
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
Optimal : <120 and < 80Normal : 120-129 and/or 80 - 84High Normal : 130-139 and/or 85-89 Pre-hypertension
Normal
Grade 1 : 140-159 and/or 90-99Grade 2 : 160-179 and/or 100-109Grade 3 : > 180 and/or > 110
Stage 1
Stage 2
ESC-ESH 2007 JNC-VII
Classification of Blood Pressure
JNC VII committee, JAMA 2003: 289;2560-2572
HYPERTENSION
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.
Blood Pressure = Cardiac Output (CO) X Peripheral Resistance (PR)Hypertension Increased CO and/or Increased PR
Excess sodium intake
Reduced Nephron number
Stress Genetic Alteration
Endothelium derived factors
Obesity
Autoregulation
Functional Constriction Structural Hypertrophy
HyperinsulinemiaCell membrane alteration
Renin Angiotensin Excess
Preload Contractility
Sympathetic nervous overactivity
Fluid Volume Venous
Constriction
Decreased Filtration surface
RenalSodium retention
Regulation of BP
Kaplan NM, Clinical Hypertension 7th ed. 2002; 63
Krakoff LR. Et al. Boca Raton; Taylor & Francis Group, 2005: 3-14.
LIFESTYLE MODIFICATIONS
INITIAL DRUG CHOICES
Not Goal BP
Without Compelling Indications With Compelling Indications
Stage 1
Thiazide-Type diuretics for most.
May consider ACEI, ARB, BB, CCB, or
combination
Stage 2
Two –Drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB
Drug(s) for the compelling indications.
Other antiHT Drugs (Diuretics, ACEI, ARB, ,
CCB) as needed
US-JNC VII Report
PROGRESSRecurrent Stroke Prevention
NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Chronic Kidney Disease
NKF-ADA Guideline, UKPDS, ALLHATDiabetes
ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST
High Coronary Disease Risk
ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
Postmyocardial Infarction
ACC/AHA Heart Failure Guideline, MERITHF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM
Heart Failure
Clinical trial basis
Recommended Drugs
Compelling Indication*
Diu
retic
BB AC
EI
AR
B
CC
B
Ald
o A
nt
Clinical Trial and Guideline Basis for Compelling Indications (JNC VII 2003)
Amlodipine besylate Extensively Studied in Large Trials
Patients studied
Comparators
Trial duration
End points: CHD death and nonfatal MI
End point: CV events and plaque progression
End point:cardiac morbidity
and mortality
ALLHATHigh-risk
hypertensive(N=33,357)
Amlodipinebesylate,lisinopril,
chlorthalidone
6 years
VALUEHigh-risk
hypertensive(N=15,245)
Amlodipinebesylate,valsartan
6 years
CAMELOT/NORMALISE
CHD patients(n=1991)
Amlodipinebesylate,enalapril, placebo
2 years
ASCOT-BPLAModerate-risk hypertensive
(N=19,342)Amlodipinebesylateperindopril,atenolol
thiazideTrial
stopped early
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
• 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.
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
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
Hypertension
M I
L V H
DeathC H F
Diastolic dysfunction
Systolic dysfunction
Normal LVStructure & Function
LV remodeling
SubclinicalLV dysfunction
OvertHeart Failure
Time (months)
Time (decades)
Vasan RS, Levy D. 1996. Arch Intern Med 156 : 1759-1796
Myocardialinfarction
Arrhythmia &loss of muscle
Remodelling
Ventriculardilatation
Congestiveheart failure
Death
Coronarythrombosis
Myocardialischaemia
CAD
AtherosclerosisLVH
Sudden Death
Risk factors Hypertension, smoking, cholesterol, diabetes
Dzau V. Braunwald E, Am Heart J. 1991
The Cardiovascular Continuum
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
pre -1980’s 1980’s 1990’s 2000’s 2020’s ⇒
Pharmacological• Digitalis• Diuretics• Vasodilators• Inotropes
Device• CRT• ICDs• LVADs• Others?
Pharmacological• Digitalis• Diuretics• Neurohormonal interventions
Non-pharmacological• Bed rest• Inactivity• Fluid restriction• (Digitalis, diuretics)
Cellular/genetic• Gene therapies• Cell implantation/ regeneration• Xenotransplantation
Heart Failure Updates, 2003
TREATMENT OPTION FOR HF
Like the carrot placed in front of the donkeyINOTROPIC
Reduce the number of sacks on the wagon
ACEI AND DIURETICS
ACE-I B Blocker
Myocardial Infarction
Preferred treatment previously
Heart Failure
Now
ß-BLOKERS
Limit the donkey’s speed, thus saving energy
ACTIVATION OF NEUROHORMONAL PATHWAYS IN HF
Ruffolo, J.Cardiovasc Pharmacol,1998
Vasoconstriction
Neurohormonal Activation• Cathecholamines• RAAS• AVP• Endothelin
Cardiac OverloadCardiomyopathyCoronary Disease
Left Ventricular Dysfunction
Peripheral organ blood flow
Skeletal muscle flow
RBFNa+ retention
Cardiac remodelling
LVhypertrophyLV dilatation
Exercise intolerance Edema, congestion Sudden death Pump failure
Renin-Angiotensin-System Blockers
Vasoconstriction
Angiotensin I
Angiotensinogen
Renin
Inactive kinins
ACE
Bradykinin
Angiotensin II
Retention of saltand water
Blood pressure increases
ACE inhibitors ACE inhibitors (ACEi)
Angiotensin IIReceptor Blokers (ARB)
KidneyLiver
XX
X
Kaplan NM, Clinical Hypertension 7th ed. 2002; 63
X Direct Renin Inhibitor
Inhibition of the RAAS by ACE inhibitors
Angiotensinogen
Angiotensin I
Angiotensin II
AT1 AT2• Vasoconstriction• Aldosterone secretion• Catecholamine release• Proliferation• Hypertrophy
• Vasodilation• Inhibition of cell growth• Cell differentiation• Injury response• Apoptosis
BP
(-)
Non-renin Non-
ACE
Renin
Angiotensin-converting
enzyme
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;Carey RM, et al. Hypertension 2000;35:155-163
Bradykinin
Inactive kinins
ACEinhibitor
BPARB
ACEI Reduced Mortality and Morbidity
Whats what 2006
6.70%6 weeks18.895 AMIGISSI3
Hospitalization 16-14%8%39-58 months3.164 CHFATLAS
progression to severe heart failure7.60%24-50 months
1.h749 AMI with LV dysfunctionTRACE
18-30%15 months2.006 AMI with HFAIRE
Overt HF 29%, Remodeling Prevented 8-16 %> 3 years
4.228 without, 2568 with overt HFSOLVD
Recurent MI 25% 19-32%24-60
months2.231 AMISAVE
Morbidity ReductionMortality
ReductionFollow upSample SizeTrials
Myocardial Insult
Myocardial Dysfunction
Increased LoadReduced Systemic Perfusion
Cardiac Adrenergic Activation
Growth and Remodeling
Apoptosis
Toxicity, Ischemia,or Energy Depletion
Altered GeneExpression
Cell Death
Necrosis
Bristow MR. Am J Cardiol 1997;80(11A):26L-40L
ADRENERGIC ACTIVATION IN MYOCARDIAL DYSFUNCTION
-Blockers in Heart Failure All-Cause Mortality
p < 0.0001
0 200 800600400
1.0
0.8
0.6
Days after inclusion
Placebo
Bisoprolol
Risk reduction = 34%
Surv
ival
0
CIBIS-II
CIBIS-II Investigators (1999)
Follow up (months)
Risk reduction = 34%p = 0.0062
0
0
3 6 9 12 16 18 21
5
10
15
20PlaceboMetoprolol CR/XL
Cum
ulat
ive
mor
talit
y (%
)
MERIT-HF
MER
IT-H
F St
udy
Gro
up.(1
999)
100
90
80
60
70
00 1512963
Placebo(n=1133)
Carvedilol (n=1156)
p 0.001
Surv
ival
(%)
Months of follow up
18 21
35% risk reduction
COPERNICUS
Pack
er e
t al.
2001
-BLOCKER THERAPY ON SURVIVAL IN CHF
NYHA II
NYHA III
NYHA IV
Ischemic
Non ischemic
0 10.5 1.5 2
Level of Evidence A
CIBIS IIMERIT-HFUS Carvedilol program
Relative Risk 95% CI
Compliance at 1 year with antihypertensive treatment
Bloom BS, et al. Clin Ther 1998;20:671-681
3843
5058
64
0
10
20
30
40
50
60
70
Diuretics Beta-blockers CCBs ACE inhibitors ARBs
Com
plia
nce
at 1
yea
r (%
)
* p<0.007 vs ACE inhibitors*
ACE, angiotensin-converting enzyme; CCB, calcium-channel blocker; ARB, angiotensin II receptor blocker
Olmesartan has greater binding affinity for the AT1 receptor than losartan
8
92
16 12
0102030405060708090
100
Olmesartan Losartan EXP3174 Candesartan
IC50
(nM
)
Koike H, et al. J Hypertens 2001;19(suppl 1):S3-S14IC50: the lower the IC50, the greater the binding affinityThese results were found in a rat study and may not be reflected in humans
Olmesartan may give more prolonged AT1 blockade than irbesartan or valsartan
0
3.16
1.781.19
1.84
0
1
2
3
4
5
Placebo Olmesartan40 mg
Irbesartan300 mg
Valsartan160 mg
Valsartan320 mg
Cha
nge
from
pre
dose
to 2
4 ho
urs
in m
ean
PRA
(ng/
mL/
h)
Jones M, et al. Presented at ASH 2006; Abstract P-195
p vs placebo <0.0001 0.005 0.058 (NS) 0.004
p vs olmesartan 0.028 0.002 0.036
n=20
PRA, plasma renin activityPerformed in healthy volunteers in 1-dose study;
PRA response may not predict those in hypertensive patients
Lower pill burden: better adherence
As the number of pre-existing Rx meds increased, the likelihood of adequately refilling AHT and LLT decreased
Number of pre-existing
Rx medications
Likelihood of achieving adherenceAdjusted odds ratio for adherence to both AHT
and LLT* (PDC ≥80%) (95%
confidence interval)
*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.
0.0 0.5 1.0 1.5 2.0 2.5
1.96 (1.72-2.25)
1.30 (1.14-1.49)
1.61 (1.40-1.84)
1.23 (1.10-1.38)
1.00 (reference group)≥6
3-5
2
1
0Greater Lesser
Fixed Dose Combination
17%
Patie
nts f
ully
com
plia
nt (%
)
Patients on free combination had a higher odds ratio (OR) of beingnon-compliant than patients on FDC: OR 2.09 (95% CI: 1.69, 2.59)
21%
Months since start of therapy
Cohort study ofgeneral practice research data (N=755)
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27
Fixed-dose combination therapyCo-administration of two pills
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• 3x1x, Pharmacokinetic/ Pharmacodynamic
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