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

Thank You