NEWER DRUGS IN CARDIOLOGY

Dr Dhirendra SinghaniaSenior consultant cardiologistPushpanjali Crosslay Hospital

Newer drugs

• Newer Anti Anginals - Ranolazine - Ivabradine

• Polypill

Chronic stable angina

THEN and NOW

Myocardial ischemia:Sites of action of anti-ischemia medication

Ranolazine

Consequences of ischemia

• Electrical instability• Myocardial dysfunction (↓ systolic function/ ↑ diastolic stiffness)

Conventionalanti-ischemicmedications ß blockers Nitrates Ca++ blockers

Compressionof nutritive

blood vessels

Ischemia(Ca2+ overload)

↑ O2 demand• Heart rate• Blood pressure• Preload• Contractility

↓ O2 supply

Development of ischemia

(Stone, 2004)

Consequences associated with dysfunction of late sodium current

• Diseases(eg, ischemia, heart failure)

• Pathological milieu(reactive O2 species,ischemic metabolites)

• Toxins and drugs(eg, ATX-II, etc.)

Na+ channel

(Gating mechanism malfunction)

• Increase ATP consumption

• Decrease ATP formation

Oxygen supply and demand

• Abnormal contraction and relaxation

• ↑ diastolic tension(↑LV wall stiffness)

Mechanicaldysfunction

• Early after potentials

• Beat-to-beat ΔAPD

• Arrhythmias (VT)

Electricalinstability

Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply

Increased myocardial tension during diastole:

– Increases myocardial O2 consumption

– Compresses intramural small vessels• Reduces myocardial blood flow

– Worsens ischemia and angina

Ranolazine: Mechanism of action

Ischemia

↑ Late INa

Na+ overload

Diastolic relaxation failure(increased diastolic tension)Extravascular compression

Ca2+ overload

Ranolazineinhibits the late inward

Na current

Monotherapy with ranolazine increases exercise performance at trough and peak: MARISA

n=175, **p <0.01 vs placebo; ***p <0.001 vs. placebo

400440480520560

Exerciseduration

Timeto angina

Time to 1-mmST

depression

Exerciseduration

Timeto angina

Time to 1-mmST

depression

Tim

e, s

ec

PeakTrough

***

******

***

******

******

*****

******

*****

*** ***

******

Placebo 500 mg bid

1000 mg bid 1500 mg bid

Chaitman et al JACC 2004;43:1375

Ch

ang

e fr

om

bas

elin

e, s

ec

n=791*p <0.05; **p ≤0.01; ***p ≤0.001 vs placebo.

50

100

150

Exerciseduration

Time to angina

Time to 1-mmST depression

Exerciseduration

Timeto angina

Time to 1-mmST depression

PeakTrough

***

** **

*****

* *

**

Placebo 750 mg bid 1000 mg bid

*

Combination regimen of ranolazine with:

► Atenolol 50 mg qd, or ► Diltiazem 120 mg qd, or ► Amlodipine 5 mg qd (CARISA)

Chaitman et al. JAMA 2004;291:309

Effect of ranolazine in patients with refractory angina despitemaximum amlodipine therapy: ERICA

0

1

2

3

4

5

6

Amlodipine+

Placebo

Amlodipine+

Ranolazine

p=0.028

Baseline On placebo On ranolazine

Amlodipine+

Placebo

Amlodipine+

Ranolazine

p=0.014

p=0.18

0.0

1.0

2.0

3.0

4.0

5.0

5.5

0.5

1.5

2.5

3.5

4.5

Stone et al. Circulation 2005;112:II-748

Angina episodes/week

Nu

mb

er o

f an

gin

a e

pis

od

es/w

eek

NTG consumption/week

p=0.48

Nu

mb

er o

f N

TG

s c

on

sum

ed/w

eek

Consistent treatment effect of ranolazine across the subgroups analyzed:

Long-Acting Nitrate (LAN) users vs non-LAN users (n=254 vs 310)

Men vs women (n=407 vs 158)

Patients aged <65 years vs ≥65 years (n=234 vs 331)

Effect of ranolazine in patients withrefractory angina despite

maximum amlodipine therapy: ERICA

Subgroup analyses

Stone et al. Circulation 2005;112:II-748

UA/NSTEMICP <48h, ST-Dep or +cTn, or DM, or TRS 3

RanolazineIV to PO

Placebo Matched IV/PO

RANDOMIZE (1:1)Double-blind

Additional endpoints: Exercise performance, extent of myocardial injury, angina questionnaire, quality of life, arrhythmia

Follow-upQ4 mo

(Avg 8-12 mo)

Holter at enrollment x 7 days

Follow-up visits: Day 14, month 4,

Q4 monthsPrimary end point

Cardiovascular death, MI or recurrent ischemia

Standard therapy

Final VisitDuration

Event-driven

MERLIN TIMI-36 (n=6500)

Ranolazine: Adverse events

Placebo (n=552)

Ranolazine (n=835)

Constipation (%) 2 8

Nausea (%) 1 4

Dizziness (%) 2 5

Headache (%) 2 3

Pts discontinuing Rx (%) 3 6

Ranolazine prolongs the QTc an average of about 6 msec.

(No episode of torsades de pointes has been observed)

Ranolazine

• Oral administration-peak plasma conc. 2-5hrs

• 75%excretedin urine, 25%-feces• Metabolized rapidly and extensively in

liver &intestine.• Terminal half life 7hrs• Steady state is generally achieved within 3

days of bid dosing.

DRUG INTERACTIONSSummary of Ranolazine drug-drug interactionsDrug Pharmacokinetic/

Pharmacodynamic Interaction

Administration Adjustments

Cimetidine No increase in ranolazine plasma concentration

No ranolazine dose adjustment is required

Ketoconazole 3.2-fold increase in average ranolazine steady-state (SS) plasma concentration

Ranolazine should not be used during ketoconazole treatment

Digoxin 1.5 –fold increase in digoxin plasma concentration

The dose of digoxin may have to be reduced when ranolazine is co-administered; no ranolazine dose adjustment is needed.

Diltiazem 1.8- to 2.3-fold increase in average ranolazine SS plasma concentration

Ranolazine should not be used during treatment with diltiazem

Rifampin Ranolazine plasma concentration reduced 95%

Co-administration with ranolazine should be avoided

Paroxetine 1.2-fold increase in average ranolazine SS plasma concentration

No ranolazine dose adjustment required

Cont.......

Drug Pharmacokinetic/ Pharmacodynamic Interaction

Simvastatin Approximate 2-fold increase in simvastatin and its active metabolite plasma concentration

Simvastatin dose may have to be reduced

Verapamil About 2-fold increase in ranolazine SS plasma concentration

Do not co-administer verapamil and ranolazine

warfarin No significant pharmacokinetic effects

No warfarin dose adjustment required

CYP3A inhibitors (potent or moderately potent

Increase in ranolazine plasma concentration

Should not be co-administered with ranolazine

CYP2D6 substrates (eg, tricyclic antidepressants, antipsychotics)

Ranolazine and/or its metabolites partially inhibit CP2D6

Lower doses of CYP2D6 substrates may be required in the presence of ranolazine

Cont…….

Drug Pharmacokinetic/ Pharmacodynamic

Interaction

Administration Adjustments

P-glycoprotein substrates

In vitro studies suggest ranolazine is an inhibitor of p-glycoprotein

The dose of p-glycoprotein substrates may have to be reduced when co-administered with ranolazine

P-glycoprotein inhibitors (eg, cyclosporine, ritonavir)

May increase absorption of ranolazine

Caution should be exercised

CYP3A and likely P-gp inducers

May decrease ranolazine plasma concentration to subtherapeutic levels

Co-administration with ranolazine should be avoided.

PATIENTS SHOULD BE ADVISED:

• That Ranolazine will not abate an acute angina episode to inform their physician of any other medications when taken concurrently with Ranolazine, including over-the-counter medications.

• That Ranolazine is only for patients not responding adequately to other antianginal drugs.

• That Ranolazine may produce changes in the electrocardiogram (QTc interval prolongation), congenital long QT syndrome, or proarrhythmic conditions such as hypokalemia.

• That Ranolazine should be avoided in patients receiving drugs that prolong the QTc interval such as class la (eg, quinidine) or Class III (eg, dofetilide, sotalol antiarrhythemic agents, erythromycin, and certain antipsychotics (eg, Thioridazine, Ziprasidone)

Cont…….

• avoided in patients receiving drugs that are potent or moderately potent inhibitors of CYP3A, including, for example, ketoconazole, HIV protease inhibitors, macrolide antibiotics, diltiazem, and verapamil.

• That grapefruit juice or grapefruit products should be avoided when taking Ranolazine.

• That Ranolazine should generally be avoided in patients with mild, moderate, or severe liver impairment.

• That Ranolazine should genrally be avoided in patients with severe renal impairment.

• That doses of Ranolazine higher than 1000mg twice a day should not be used.

• That if a dose of Ranolazine is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled.

Cont.......

• That Ranolazine may be taken with or without meals.

• That Ranolazine tablets whould be swallowed whole and not crushed, broken , or chewed to contact their physician if they expeience palpitations or fainting spells while taking Ranolazine.

• That Ranolazine may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile, or machinery, or engag in activities requiring mental alertness or coordination. Se tablets).

THEN and NOW

Chronic stable angina

•Diaz A, et al. Diaz A, et al. Eur Heart J.Eur Heart J. 2005;26:867-874. 2005;26:867-874.

•The CASS registry: n=24 913; 14.1-year follow-up

Elevated resting heart rate isassociated with higher mortality in CAD

•Adjusted survival curves forcardiovascular mortality

•Adjusted survival curvesfor overall mortality

•0 •5 •10 •15 •20

•0.5

•0.6

•0.7

•0.8

•0.9

•1.0

•C

um

ula

tive s

urv

ival

•Years after enrolmentYears after enrolment

•=<62 •=>83 bpm

•P<0.0001

•0 •5 •10 •15 •20

•0.5

•0.6

•0.7

•0.8

•0.9

•1.0

•P<0.0001

•C

um

ula

tive s

urv

ival

•Years after enrolmentYears after enrolment

•Cucherat Ml. Eur Heart J. 2007;28:3012-3019.

•Meta-regression of 12 controlled studies

Heart rate reduction is associated witha decrease of post-MI cardiac deaths

•Absolute heart rate reduction (bpm)

•O

dds

rati

o

•0.1

•0.2

•0.5

•1.0

•2.0

•-5 •-10 •-15 •-20•0

•ββ-Blockers

•Calcium channel blockers

•P<0.00042

IVABRADINE

• Ivabradine acts by reducing the heart rate in a mechanism different from beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs .

• Ivabradine acts on the If (f is for "funny ion current, which is highly expressed in the sinoatrial node.

• If is a mixed Na+–K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system

IIVABRADINE

• Most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node.• Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood to flow to the myocardium.• dose of 5 mg twice daily is recommended initially, with increase to 7.5 mg if necessary and tolerated. in the elderly, the manufacturer recommends a starting dose of 2.5 mg.

IVABRADINE

INITIATIVE: Study design

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.ET = exercise test (treadmill) *ET at trough and 4 hours post-dose

4 weeks 12 weeks 2 weeks

Atenolol50 mg(n = 307)

Ivabradine5 mg bid(n = 315)

Ivabradine5 mg bid(n = 317)

10 mg bid

7.5 mg bid

100 mg50 mg

25 mg

Placebo

Placebo

7 days2–7 days

Washout Run-in

Selection ET

Inclusion ET ET* ET*

Placebo

International Trial on the Treatment of Angina with Ivabradine vs. Atenolol

INITIATIVE

INITIATIVE: Effects of ivabradine vs β-blockade on primary outcome

78.8

86.8

91.7

0

75

80

85

90

95

Atenolol Ivabradine Ivabradine

Change in exercise duration

(seconds)

100 mg(n = 286)

7.5 mg bid(n = 300)

10 mg bid(n = 298)

P < 0.001 for noninferiority vs atenolol (both ivabradine doses)

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.Patients completing trial

INITIATIVE

INITIATIVE: Summary

• Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol 100 mg as measured by– Total exercise duration– Time to limiting angina, angina onset, and 1 mm ST

• Most common adverse events were transient visual symptoms, mainly increased brightness in limited areas

• Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients

If current inhibition may be as effective as β-blockade in treatment of stable angina

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

Ivabradine

• highly water soluble,rapidly absorbed,peak plasma levels in 1 hr in fasting condition.

• Taken up with meals• Extensively metabolizedby liver and gut by

oxidation through cytochrome CYP3A4.• Effective half life 11hrs• Contraindications- hypersensitivity, bradycardia,

sss, cardiogenic shock, AMI, severe hepatic insufficiency, severe hypotension.

• Commonest side effect luminous phenomena

Ivabradine shows efficacy, tolerability in diabetics with stable CAD13 November 2009

MedWire News: Ivabradine is effective for preventing angina in patients with diabetes mellitus and stable coronary artery disease (CAD), and has no impact on glucose metabolism, an analysis of clinical trial data shows.

The study supports a potential role for ivabradine as an alternative to beta blockers in the

treatment of stable angina, say the study authors writing in the American Journal of Cardiology.

Ivabradine is a specific heart-rate-lowering antianginal agent that inhibits the If current, the primary modulator of spontaneous diastolic depolarization in the sinoatrial node. The drug has been evaluated in a clinical development program involving approximately 3000 patients with stable CAD, most of whom had angina.

Medwire news contd.

• As in non-diabetic individuals, ivabradine treatment in diabetic patients was associated with an approximately 15% reduction in resting heart rate and an improvement in exercise tolerance measures, including total exercise duration, time to onset of myocardial ischemia, and time to onset of angina.

Ivabradine therapy in diabetics was also associated with a reduction in the frequency of angina attacks but without any increase in rates of sinus bradycardia or visual disturbances (both known to be related to the action of ivabradine). Furthermore, ivabradine had no adverse impact on glucose metabolism or other safety/tolerability outcomes.

“Ivabridine is effective in patients with diabetes mellitus and angina and is not associated with particular safety concerns or adverse effects on glucose metabolism in this population. Therefore, ivabradine represents an attractive alternative to beta-blockers.”

Am J Cardiol 2009; Advance online publication

The concept and the appeal of Polypill

• Aspirin, β-blockers, angiotensin-converting-enzymeinhibitors, and statins reduce cardiovascular disease.

• One combination pill including all the above drugs could potentially reduce recurrent vascular events in people with cardiovascular disease by about 75%

Yusuf S. Two decades of progress in preventing cardiovascular disease. Lancet 2002; 360: 2–3.

The concept and the appeal of Polypill-compliance benefits

• Adherence to treatment is poor even among those who have experienced a CVD event and non-adherence is associated with worse outcomes

• For primary prevention, adherence to treatment is an even greater challenge than for those who have had a major event

– Convincing people who feel well, that they need lifestyle change or lifelong drug treatment requires high quality information and Communication

• The polypill could fit well into more modern medical systems, in which large proportions of patients with risk factors are untreated

• Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, for the EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009; 373: 929–40.

• Ref: http://www.nice.org.uk/nicemedia/pdf/CG67FullGuideline1.pdf

Polypill and Cardiovascular Polypill and Cardiovascular PreventionPrevention

““Overall, the evidence suggests that fixed-dose combination pills and unit-of-Overall, the evidence suggests that fixed-dose combination pills and unit-of-use packaging are likely to improve adherence” use packaging are likely to improve adherence”

J Connor et al. Bulletin WHO December 2004J Connor et al. Bulletin WHO December 2004

““This expert panel believes that the concept of CP shows sufficient This expert panel believes that the concept of CP shows sufficient promise to justify the additional scientific testing of its potential public promise to justify the additional scientific testing of its potential public health applications”health applications”

Combination Pharmacotherapy and Public Health WGCombination Pharmacotherapy and Public Health WG

““It is strongly recommended that a research agenda should be established It is strongly recommended that a research agenda should be established to produce and test FDC products for secondary prevention of heart attack to produce and test FDC products for secondary prevention of heart attack and stroke to improve adherence and prevent mortality and morbidityand stroke to improve adherence and prevent mortality and morbidity” ”

Kaplan Kaplan Laining. Priority Medicines for Europe and the World 2004Laining. Priority Medicines for Europe and the World 2004

• A strategy to reduce cardiovascular disease by more than A strategy to reduce cardiovascular disease by more than 80%. (N.J. Wald, M.R. Law, BMJ 2003)80%. (N.J. Wald, M.R. Law, BMJ 2003)

The challenges

• Could the Polycap be formulated?• If so, what molecule should it contain from each class of

drug?• What strength of each molecule should be used?• Would it be too large to swallow?• Will it be a stable formulation?• Will these drugs interact with each other inside the

Polycap?• Do we need 3 antihypertensives?• Will nearly healthy people take this Polycap?• Will the individual drugs in the Polycap work?• Will the Polycap be safe? (Adverse Events)

Can it reduce risk factors and CVD substantially?

Formulating a polypill-Is it a mere “add this to that”?

• Stability testing

• Pharmacokinetic analysis

– Bioavailability of drugs when given as polycap vs those when given individually

• Efficacy

– To see for the individual effects and contributions of each component to the

overall efficacy

• Drug interactions

• Safety

TIPS : The Indian Polycap Study

TIPS: Components of the Polycap

Antiplatelet ASA 100 mg/d

Statin Simvastatin 20 mg/d

ACE-Inhibitors Ramipril 5 mg/d

Beta-blocker Atenolol 50 mg/d

Diuretic Hydrochlorothiazide 12.5 mg/d

TIPS: Composition of the eight comparator groups

1) ASP: Aspirin (100 mg)

2) T: Thiazide (12.5 mg)

3) T + R: Thiazide (12.5mg) Ramipril (5mg)

4) T + At: Thiazide (12.5mg) Atenolol (50mg)

5) R + At: Ramipril (5mg) Atenolol (50 mg)

6) T + R + At: Thiazide (5mg) Ramipril (5 mg) Atenolol (50 mg)

7) T+R+At+ASA:Above (6) + ASA100 mg

8) S Simvastatin 20 mg

TIPS: Study Design

• Randomized and double blind • Polycap vs. 8 other formulations• Superiority and inferiority comparisons• Active treatment for 12 weeks• Wash out for 4 weeks• Impact on BP, HR, lipids, urine thromboxane B2• Safety and tolerability.• Parallel PK study.

Combinations and comparisons

Composition of comparators Type of comparison

Thiazide 12.5mg + Ramipril 5mg + Atenolol 50mg

Non-inferiority (BP)

Thiazide 12.5mg + Ramipril 5mg + Atenolol 50mg + Aspirin 100mg

Non-inferiority (BP, Platelet inhibition)

Aspirin 100mg Non-inferiority (Platelet inhibition )

Simvastatin 20mg Non-inferiority (lipid lowering)

Hydrochlorothiazide 12.5mg Superiority (BP)

Thiazide12.5mg+Ramipril 5mg Superiority (BP)

Thiazide12.5mg +Atenolol 50 mg Superiority (BP)

Ramipril 5 mg + Atenolol 50 mg Superiority (BP)

TIPS: Primary Objectives

Whether the Polycap is equivalent :

1. In reducing BP when compared with its components containing 3 BP lowering drugs (HCTZ, atenolol, ramipril)

2. In reducing HR when compared with atenolol

3. In modifying lipids when compared with simvastatin alone

4. In suppressing urine thromboxane B2 vs ASA alone

5. In its rates of adverse event when compared with its equivalent components

TIPS: Secondary Objectives

• Whether Polycap is superior in reducing BP compared to its components containing

– One BP lowering drug (thiazide) or

– Two BP lowering drugs

• HCTZ + Ramipril

• HCTZ + Atenolol

• Ramipril + Atenolol

Power for Non-Inferiority Comparisons for the Key Outcomes

OutcomesComparison of Treatment

Arms

Non-Inferiority

Margin (SD)

1-sided type 1 error

Power

BP: Diastolic BP P vs TRAt or TRAtAs

2 (6) mm Hg

0.025 94%

Lipids (LDL chol) P vs S 0.155 (0.46)

mmol/L

0.025 97%

Antiplatelet therapy (Urinary Thromboxane B2)

P vs TRAtAs 60 (181) 0.025 96%

TIPS: Statistcal methods

• Intention to treat.• All post- rand variables utilized by a

repeated measures approach.• Results are baseline and “control” group

subtracted.• When 12 week BP, HR or lipids were

missing, we used earlier measures resulting in 96% BP data and 91% lipid data.

TIPS: Organization

53 Centers in India

Indian Coordinating CenterSt. John’s Medical College, Research

Institute,

International Coordinating Center Population Health Research Institute

HHS and McMaster University, Hamilton, Canada

Sponsor - Cadila Pharma, India

Steering committee

TIPS: Target Population

Inclusion Criteria: • Age 45 to 80 years• At least one CV risk factor

• Hypertension (SBP > 140 ≤ 159; DBP > 90 ≤ 100Hg, but treated)• Diabetes mellitus (on one oral drug / diet)• Smoker > 5 years• Raised WHR• Abnormal lipids (LDL 130-175mg/dl)

• Informed consent

Exclusion Criteria:• On study meds and cannot be stopped• 2 or more BP lowering meds• LDL >175mg/dl• Abnormal renal function (Cr>2.0mg/dl or K+>5.5 mEq/L)• Previous CVD or CHF

TIPS: Study Flow

Screening (stabilization and baseline assessments)

3 weeks

Randomization (BP, HR, urine, lipids)

7 to 10 days (BP, HR)

4 weeks (BP, HR)

8 weeks (BP, HR)

12 weeks (BP, HR, urine, lipids)

Washout 16 weeks (BP, HR)

Final treatment allocation

2053

Polycap - 412

As - 205

T - 205

TR - 209

TAt - 207

RA - 205

TAR - 204

TAtRAs - 204

S - 202

Flow Chart of the Study and Data Completeness

No. randomized = 2053

No. final visit = 86%

No. with post rand HR/BP = 96%

No with post rand lipids at anytime

= 91% (81%)*

*At scheduled end

Inclusion criteria

Total patients randomized 2053

HTN 1297(63.2)

Type-2 DM 696(33.9)

Current smoker>5yrs 240(11.7)

High WHR 1501(73.1)

Abnormal lipids 676(32.9)

TIPS: Selected Baseline Characteristics

Characteristics Overall

N 2053

Age 54.0 (7.9)

BMI 26.3 (4.5)

Heart rate (beats/min) 80.1 (10.7)

Diabetes 33.9%

Current Smoker 13.4%

Females 43.9%

Calcium Channel Blockers 21.7%

TIPS: Selected Baseline Characteristics

Characteristics Overall

N 2053

Systolic BP (mmHg) 134.4 (12.3)

Diastolic BP (mmHg) 85.0 (8.1)

Total Cholesterol (mmol/d) 4.7 (0.9)

LDL (mmol/L) 3.0 (0.8)

HDL (mmol/L) 1.1 (0.3)

Triglycerides (mmol/L) 1.9 (1.2)

ApoB 0.9 (0.2)

ApoA 1.2 (0.2)

Results

Mean Changes in BP (95% CI) vs 0 Drugs

Reductions (mmHg)

SYS DIA

1 BP lowering -2.2 -1.3

2 BP lowering -4.7 -3.6

3 BP lowering -6.9 -5.0

Polycap -7.4 -5.6

Treatment

Ch

an

ge

in

sittin

g S

BP

(95

% C

I)

-14

-12

-10

-8-6

-4-2

0

As T TR TAt RAt TRAt TRAtAs S P

Treatment

Ch

an

ge

in

sittin

g D

BP

(9

5%

CI)

-14

-12

-10

-8-6

-4-2

0

As T TR TAt RAt TRAt TRAtAs S P

Treatment

Ch

an

ge

in

sittin

g S

BP

(95

% C

I)

-14

-12

-10

-8-6

-4-2

0

As,S T TR,TAt,RAt TRAt,TRAtAs Polycap

Treatment

Ch

an

ge

in

sittin

g D

BP

(95

% C

I)

-14

-12

-10

-8-6

-4-2

0

As,S T TR,TAt,RAt TRAt,TRAtAs Polycap

No Anti-ht

Change in SBP/DBP

Visit

Ch

an

ge

in S

ittin

g S

BP

-10

-50

Rand W 2 W 4 W 8 W 12 W 16(End of Trt)

As,STTR,TAt,RAtTRAt,TRAtAs,P

Visit

Ch

an

ge

in S

ittin

g D

BP

-10

-50

Rand W 2 W 4 W 8 W 12 W 16(End of Trt)

As,STTR,TAt,RAtTRAt,TRAtAs,P

Change in SBP DBP

Impact of Atenolol arms vs Polycap on Heart Rate

Reduction in HR

CI P

Polycap -7.0 (-6.3 to -7.7) 0.001

Other Atenolol arms

-7.0 (-6.2 to 7.9) 0.001

Non Atenolol arms 0.0 (-0.84 to 0.85)

0.99

Polycap/Other atenolol vs non-atenolol arms <<0.0001

Cha

nge

in S

ittin

g H

R(9

5% C

I)

-10

-8-6

-4-2

02

Non-Atenolol TAt,RAt,TRAt,TRAtAs Polycap

- + - + - +

By baseline HR(<81 vs >=81)

Effect on Heart Rate

Impact on LDL

Mean CI %

Simvastatin : -0.83 mmol -0.94 to -0.74 27.7%

Polycap : -0.70 mmol -0.78 to -0.64 23.3%

Differences: -0.13 mmol (-0.25 to -0.01) 4.4%

Differences vs both simvastatin arms compared to non-statin p<0.001

Effect not clinically significant

LDL change with Polycap vs Simvastatin p=0.04

Parallel impact on ApoB: Simv: -0.21 mmol/L vs Polycap : -0.18 mmol/L (Diff of 0.03 mmol; p=0.06).

Treatment

Cha

ng

e in

Tot

al C

ho

lest

ero

l(9

5% C

I)

-1.0

-0.6

-0.2

0.2

As T TR TAt RAt TRAt TRAtAs S P

Treatment

Cha

ng

e in

LD

L(9

5% C

I)

-0.8

-0.4

0.0

As T TR TAt RAt TRAt TRAtAs S P

Treatment

Cha

ng

e in

Apo

B(9

5%

CI)

-0.2

0-0

.10

0.0

As T TR TAt RAt TRAt TRAtAs S P

Treatment

Cha

ng

e in

HD

L (

95

% C

I)

-0.0

8-0

.04

0.0

0.0

4

As T TR TAt RAt TRAt TRAtAs S P

Effect on LDL

Chan

ge in

LDL

(95%

CI)

-1.0

-0.5

0.0

Non-Statin Simvastatin Polycap

- + - + - +

Baseline LDL(<3.4 vs >=3.4)

Cha

nge

in L

DL(

95%

CI)

-1.0

-0.5

0.0

Non-Statin Simvastatin Polycap

- + - + - +

By Diabetic status(No vs Yes)

Change in LDL by Baseline LDL and Diabetic Status

TIPS: Impact of Various Treatments on Urinary Thromboxane B2

Mean CI

ASA alone -388.0 (-453 to -322) P <0.001 vs baseline

3 BP lowering drugs + ASA

-389.2 (-457 to -321)

Polycap -322.3 (-369 to 276)

Selected safety parameters (%)

Ov As T TR TAt RA TRA TR AtAs

S P

Dizziness 4.5 4.9 3.9 1.9 2.9 5.4 5.4 5.4 2.5 6.3

Cough 3.8 1.5 3.4 7.2 0.5 3.9 3.9 5.9 1.0 5.3

Fatigue 1.8 1.0 2.0 1.4 1.9 2.0 3.4 0.5 2.0 1.7

Bradycardia 0.2 0 0 0 1.0 0 0.5 0.5 0 0.2

Cr>50% Rnd 8.3 9.3 6.8 7.7 9.7 7.3 7.4 10.3 7.9 8.5

Potasm>5.5 5.3 5.9 4.4 5.3 4.8 5.9 7.4 6.9 3.5 4.4

SGPT>2 ULN 1.0 0.5 0.5 3.3 1.9 1.0 0 0.5 1.5 0.5

Reasons for drug discontinuations Temporary or Permanent (%)

Ov As T TR TAt RAt TRA TR AtAs

S P

Soc/ refused 21.8 22.9 22.0 21.5 16.4 22.0 27.0 24.5 23.8 19.2

Dizz/ HoT 3.4 2.9 3.4 1.0 1.9 4.4 4.4 4.4 3.0 4.4

Gastr/ dysp 1.4 1.5 1.0 2.4 1.0 1.5 1.0 1.5 1.5 1.2

Hyperkalem 0.2 0 0 0 0 0.5 0.5 0.5 0 0.2

Cough 0.9 0.5 0.5 2.4 0 1.0 0.5 1.5 0 1.5

Drug intol (other) 0.5 0.5 0.5 1.0 0 0.5 0 1.5 0 0.5

Bradycard 0.2 0 0 0 0.5 0.5 0 0.5 0 0.5

Other 6.3 6.8 4.9 4.8 6.3 7.8 7.8 7.4 3.5 7.0

Total 29.8 28.3 28.0 27.8 24.2 31.2 35.8 33.8 28.2 29.9

TIPS: Reasons for Permanent Discontinuation of Study Drug

0

5

10

15

20

25

30

As,S,T TR,Tat,RAt TRAt TRAtAs Polycap

Per

cent

Polycap: Reasons for Permanent Discontinuation

Other Reasons

Specific Reasons

Social Reasons/Refusals

Estimated reductions in CHD/Stroke of a Polycap in Those With Average Risk Factor Levels

% Relative Reduction

Reduction in Risk Factors

CHD Stroke

LDL-C (mmol/L) Est (Simv 20) 0.80 27% 8%

DBP (mmHg) Est (3, ½ dose)

5.7 24% 33%

Platelet function Est (ASA 100

mg)Similar 32%* 16%

Combined Est - 62% 48%

*RCTs suggest a smaller benefit

TIPS: Strengths

• 9 Arms

– Ability to understand impact of specific components of Polycap

• Comprehensive evaluation of

– Safety (glucose, SGPT, clinical) and

– Efficacy (BP, HR, lipids, TBx2)

• Provides substantial information for the development of a clinically useful Polycap

TIPS: Summary

In those with average risk factor levels,

• The Polycap is similar to the added effects of each of its 3 BP lowering components.

• There is greater BP lowering with incremental components.

• ASA does not interfere with the BP lowering effects.

• The Polycap reduces LDL to a slightly lower extent compared to simvastatin alone

• The Polycap lowers thromboxane B2 to a similar extent as aspirin alone.

• There are no significant drug-drug interactions

• The Polycap is well tolerated.

• The Polycap could potentially reduce CVD risk by about half.

Impact of Polycap

Advantages of the Polycap

• Improved compliance of both physicians and patients

• Decreased costs• Increased access: Non-physicians prescribe /OTC

and physicians deal with resistant or complex situations and adverse effects

• A basis for promoting prudent lifestyle.• Potential large reductions in vascular events

Who could benefit from the Polycap?

• Populations: Those with vascular disease? those at hi risk( eg DM, etc)? those over the age of 55?

• Settings: • Mid and low income countries or all?• Physician based or non-physician based?• Prescription or OTC?

Impact of Polycap in India

• 70% of the Indians reside in the rural areas

• CVD - the leading cause of mortality, accounting for at least 32%

of all deaths.

• 51% of all CV deaths occurred in patients <70 years of age 1

• Prevalence of CHD was estimated to be 4.8% (95% CI, 4.1 to 5.)

• The prevalence of CeVD was estimated at 2.0% (95% CI, 1.5 to

2.4) 1

Rohina Joshi, Clara K. Chow,P. Krishnam Raju et al ; Fatal and Nonfatal Cardiovascular Disease and the Use of

Therapies for Secondary Prevention in a Rural Region of India

Suboptimal management of CVD

• Among individuals with either diagnosis,

– 14% (95% CI, 10 to 18) reported taking aspirin,

– 41% (95% CI, 36 to 47) took a blood pressure-lowering medication

– Only 5% (95% CI, 3 to 7) reported using a cholesterol-lowering medication 1

• Polycap can be a safe and comprehensive option to

optimize the treatment

Rohina Joshi, Clara K. Chow,P. Krishnam Raju et al ; Fatal and Nonfatal Cardiovascular Disease and the Use of Therapies for Secondary Prevention in a Rural Region of India

“Why does the Polypill make everybody mad?”

• Makes prevention very easy: Challenges the established mantra of “tailoring” drugs and doses to the individual.

• Challenges the need for physicians to be involved in prevention.

• Costs of prevention will SUBSTANTIALLY decrease: challenges the dominance of BIG PHARMA.

• Anti-establishment.

IVABRADINE

INITIATIVE: Study design

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.ET = exercise test (treadmill) *ET at trough and 4 hours post-dose

4 weeks 12 weeks 2 weeks

Atenolol50 mg(n = 307)

Ivabradine5 mg bid(n = 315)

Ivabradine5 mg bid(n = 317)

10 mg bid

7.5 mg bid

100 mg50 mg

25 mg

Placebo

Placebo

7 days2–7 days

Washout Run-in

Selection ET

Inclusion ET ET* ET*

Placebo

International Trial on the Treatment of Angina with Ivabradine vs. Atenolol

INITIATIVE

INITIATIVE: Effects of ivabradine vs β-blockade on primary outcome

78.8

86.8

91.7

0

75

80

85

90

95

Atenolol Ivabradine Ivabradine

Change in exercise duration

(seconds)

100 mg(n = 286)

7.5 mg bid(n = 300)

10 mg bid(n = 298)

P < 0.001 for noninferiority vs atenolol (both ivabradine doses)

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.Patients completing trial

INITIATIVE

INITIATIVE: Summary

• Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol 100 mg as measured by– Total exercise duration– Time to limiting angina, angina onset, and 1 mm ST

• Most common adverse events were transient visual symptoms, mainly increased brightness in limited areas

• Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients

If current inhibition may be as effective as β-blockade in treatment of stable angina

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

Ivabradine shows efficacy, tolerability in diabetics with stable CAD13 November 2009

MedWire News: Ivabradine is effective for preventing angina in patients with diabetes mellitus and stable coronary artery disease (CAD), and has no impact on glucose metabolism, an analysis of clinical trial data shows.

The study supports a potential role for ivabradine as an alternative to beta blockers in the

treatment of stable angina, say the study authors writing in the American Journal of Cardiology.

Ivabradine is a specific heart-rate-lowering antianginal agent that inhibits the If current, the primary modulator of spontaneous diastolic depolarization in the sinoatrial node. The drug has been evaluated in a clinical development program involving approximately 3000 patients with stable CAD, most of whom had angina.

Medwire news contd.

• As in non-diabetic individuals, ivabradine treatment in diabetic patients was associated with an approximately 15% reduction in resting heart rate and an improvement in exercise tolerance measures, including total exercise duration, time to onset of myocardial ischemia, and time to onset of angina.

Ivabradine therapy in diabetics was also associated with a reduction in the frequency of angina attacks but without any increase in rates of sinus bradycardia or visual disturbances (both known to be related to the action of ivabradine). Furthermore, ivabradine had no adverse impact on glucose metabolism or other safety/tolerability outcomes.

“Ivabridine is effective in patients with diabetes mellitus and angina and is not associated with particular safety concerns or adverse effects on glucose metabolism in this population. Therefore, ivabradine represents an attractive alternative to beta-blockers.”

Am J Cardiol 2009; Advance online publication

0

1

2

3

4

5

6

0

10

20

30

Placebo + Amlodipine Ranolazine + Amlodipine

Anginafrequency

NTGuse

Anginafrequency

NTGUse

Angina frequency domain(Seattle Angina Questionnaire)

p<0.001p=0.57p<0.001

p=0.029

p=0.036

p=0.28

≤4.5 anginaepisodes/week

>4.5 anginaepisodes/week

≤4.5 anginaepisodes/week

>4.5 anginaepisodes/week

Subgroup analyses: Frequency of angina

Effect of ranolazine in patients withrefractory angina despitemaximum amlodipine therapy: ERICA

Nu

mb

er/W

k

Ch

ang

e f

rom

Bas

elin

ein

SA

Q S

core

Stone et al. Circulation 2005;112:II-748