koenig aeha2005 short

Emerging Atherosclerosis Drugs to Watch Emerging Atherosclerosis Drugs to Watch and Challenges and Promises of “PolyPill”and Challenges and Promises of “PolyPill”

Wolfgang Koenig, MD, FRCP, FESC, FACCWolfgang Koenig, MD, FRCP, FESC, FACCDept. of Internal Medicine II - CardiologyDept. of Internal Medicine II - Cardiology

University of Ulm Medical CenterUniversity of Ulm Medical CenterUlm, GermanyUlm, Germany

Association for Eradication of Heart AttackAssociation for Eradication of Heart Attack““From Vulnerable Plaque to Vulnerable Patient” SummitFrom Vulnerable Plaque to Vulnerable Patient” SummitA satellite event during the annual scientific sessions of the AHAA satellite event during the annual scientific sessions of the AHA

Saturday, November 12th, 2005,Dallas, TXSaturday, November 12th, 2005,Dallas, TX

Cardiovascular Drugs To WatchCardiovascular Drugs To

WatchCardiovascular Drugs To WatchCardiovascular Drugs To



Watch

Cardiovascular Drugs To Watch

Direct and Indirect Effects Direct and Indirect Effects of PPAR Nuclear Receptorsof PPAR Nuclear Receptors

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Dormandy et al. Lancet 2005;366:1279-1289Dormandy et al. Lancet 2005;366:1279-1289

3-Year Kaplan-Meier Estimate3-Year Kaplan-Meier Estimate

Pioglitazone (%)Pioglitazone (%) Placebo (%)Placebo (%) RR (%)RR (%) PP

Primary endpointPrimary endpoint 21.021.0 23.523.5 1010 0.0950.095Principal secondary endpoint*Principal secondary endpoint* 12.312.3 14.414.4 1616 0.0270.027

Prospective, multi-centre, randomised, double-blind, placebo-controlled, Prospective, multi-centre, randomised, double-blind, placebo-controlled, parallel-group study parallel-group study Planned recruitment of 5000 patientsPlanned recruitment of 5000 patients Minimum of 2.5 years exposure to treatmentMinimum of 2.5 years exposure to treatment Event driven: >760 endpoint events Event driven: >760 endpoint events

• 90% power to detect a 20% reduction in the hazard rate90% power to detect a 20% reduction in the hazard rate Existing therapy continued with diet and glucose-lowering agents, as well as Existing therapy continued with diet and glucose-lowering agents, as well as antihypertensives, lipid-altering agents, antithrombotic agents antihypertensives, lipid-altering agents, antithrombotic agents Patient management throughout study to be according to the 1999 International Patient management throughout study to be according to the 1999 International Diabetes Federation (Europe) Guidelines Diabetes Federation (Europe) Guidelines

*All-cause mortality, non-fatal MI and stroke*All-cause mortality, non-fatal MI and stroke

Pioglitazone Reduces Neointima Volume Pioglitazone Reduces Neointima Volume After Coronary Stent ImplantationAfter Coronary Stent Implantation

Day 1Day 1start of treatmentstart of treatmentstent implantationstent implantation

RandomizationRandomization

PlaceboPlacebo

PioglitazonPioglitazon30 mg OD30 mg OD

6 months6 monthsIVUSIVUS

Intravascular ultrasound (IVUS) Intravascular ultrasound (IVUS) •IVUS-catheter:IVUS-catheter: UltraCross™ 2.9F, UltraCross™ 2.9F,

30 mHz (Boston Scientific Scimed)30 mHz (Boston Scientific Scimed)• automated pullback at 0,5 mm/secautomated pullback at 0,5 mm/sec• computer-based contour detection programcomputer-based contour detection program (Medis Medical Imaging System) (Medis Medical Imaging System) • analysis: analysis:

• stented segmentstented segment• 5 mm proximal and distal 5 mm proximal and distal

of the stented segment of the stented segment

Study designStudy design

StentStent

NeointimaNeointima

Marx, Koenig et al. Circulation 2005;112:2792-2798Marx, Koenig et al. Circulation 2005;112:2792-2798

00

11

22

33

44

55

PlaceboPlacebo

Neoi

ntim

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olum

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imal

vol

ume

(mm

³/mm

)(m

m³/m

m)

PioglitazonePioglitazone

**3.1±1.63.1±1.6

2.3±1.12.3±1.1

* P<0.05 for comparison * P<0.05 for comparison of parameters between groupsof parameters between groups

Tota

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Tota

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(mm

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)(m

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PlaceboPlacebo PioglitazonePioglitazone

**13.2±4.213.2±4.2

11.2±3.211.2±3.2

* P<0.05 for comparison * P<0.05 for comparison of parameters between groupsof parameters between groups

StentStent

00

55

1010

1515

2020


Tota

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que

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Tota

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que

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(mm

³/mm

)(m

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proximalproximal

10.4±4.010.4±4.07.8±3.47.8±3.4

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8.1±4.38.1±4.36.0±3.06.0±3.0

Effect of Pioglitazone on Neointima and on Total Effect of Pioglitazone on Neointima and on Total Plaque Volume Formation After 6 monthsPlaque Volume Formation After 6 months

Marx, Koenig et al. Circulation 2005;112:2792-2798Marx, Koenig et al. Circulation 2005;112:2792-2798

CytokinesCytokinesPlaque Plaque

FormationFormation

Foam CellFoam Cell

MonocytesMonocytes

MacrophageMacrophage

LUMENLUMEN

MEDIAMEDIA

INTIMAINTIMA

Oxidized LDLOxidized LDL

Adhesion Adhesion MoleculesMolecules

Lyso-PCLyso-PCOxFAOxFA

Lp-PLALp-PLA22

Role of Lp-PLARole of Lp-PLA22 in Coronary Heart Disease in Coronary Heart Disease

Area

(mm

Area

(mm

22 ))Th

ickne

ss (m

m)

Thick

ness

(mm

)

Median LesionMedian LesionCross-sectional AreaCross-sectional Area

Median Lesion Median Lesion ThicknessThickness

In Pre-Clinical Studies, Inhibition of the Enzyme In Pre-Clinical Studies, Inhibition of the Enzyme Slows Atherosclerotic Disease ProgressionSlows Atherosclerotic Disease Progression

Effect of SB-244323 (10mg/kg/day) on aortic lesions in WHHL rabbitsEffect of SB-244323 (10mg/kg/day) on aortic lesions in WHHL rabbits

**

**

*p<0.03*p<0.03

0.180.180.160.160.140.140.120.120.100.100.080.080.060.060.040.040.020.020.000.00

ControlControlSB-244323SB-244323

Benson et al. Atherosclerosis 2000;151:166Benson et al. Atherosclerosis 2000;151:166

-100-100

-80-80

-60-60

-40-40

-20-20

0040 mg40 mg 80 mg80 mg

N=103N=103% C

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(Lp-

PLA 22))

Circulating Lp-PLACirculating Lp-PLA22::Healthy volunteers: selective Healthy volunteers: selective Lp-PLALp-PLA22 inhibitors produce inhibitors produce dose-dependent inhibition up dose-dependent inhibition up to to 95%95%Patients: dose-dependent Patients: dose-dependent inhibition up to 80% (14-28d)inhibition up to 80% (14-28d)

Plaque Lp-PLAPlaque Lp-PLA22

Dose-dependent enzyme Dose-dependent enzyme inhibition (14d) independent inhibition (14d) independent of concomitant statin therapyof concomitant statin therapy

Clinical Experience with Lp-PLAClinical Experience with Lp-PLA22 Inhibitors: Inhibitors:SB-480848 Decreases Plasma and Plaque ActivitySB-480848 Decreases Plasma and Plaque Activity

Plasma ActivityPlasma Activity Plaque ActivityPlaque Activity

Pre-surgical dosing in patients undergoingPre-surgical dosing in patients undergoingcarotid endarterectomycarotid endarterectomy

Johnson et al. Johnson et al. Circulation 2004:110(suppl III):III-590Circulation 2004:110(suppl III):III-590

Lp-PLALp-PLA22: A More Specific Marker of : A More Specific Marker of Vascular Inflammation?Vascular Inflammation?

Mechanistic studies Mechanistic studies - role in formation of human atheroma- role in formation of human atheroma - impact of Lp-PLA- impact of Lp-PLA22 inhibition in relevant tissues inhibition in relevant tissues

Clinical index of risk (surrogate endpoints)Clinical index of risk (surrogate endpoints)

- plaque imaging: structural vs compositional - plaque imaging: structural vs compositional - plasma biomarkers & global approach…omics- plasma biomarkers & global approach…omics

Outcome studies: closing therapeutic gap in „post HPS/PROVE-IT era“:Outcome studies: closing therapeutic gap in „post HPS/PROVE-IT era“:

- high risk populations: post ACS, metS/diabetes, renal impairment… - high risk populations: post ACS, metS/diabetes, renal impairment…

May represent a link between lipid metabolismMay represent a link between lipid metabolism and inflammationand inflammation

Observational studies (clinical endpoints) inObservational studies (clinical endpoints) in diverse populations with varying absolute riskdiverse populations with varying absolute risk

Rimonabant – a Selective Type 1 Rimonabant – a Selective Type 1 Cannabinoid-Receptor-AntagonistCannabinoid-Receptor-Antagonist

RimonabantRimonabant

Effects on central nervous Effects on central nervous system system

Metabolic effectsMetabolic effects

Nutrient intakeNutrient intake AdiponectinAdiponectinSmokingSmoking

Body weightBody weightWaist girthWaist girth

Oxidation of fatty Oxidation of fatty acids and -excretionacids and -excretion Insulin sensitivityInsulin sensitivity

HDLHDL

CRPCRP

TriglyceridesTriglycerides

Spieker et al. Kardiovaskuläre Medizin 2005;8:18–22Spieker et al. Kardiovaskuläre Medizin 2005;8:18–22

ITT LOCF 5 mg vs placebo:nsITT LOCF 5 mg vs placebo:ns 20 mg vs placebo: p=0.00320 mg vs placebo: p=0.003

BaselineBaseline 1 Year1 Year

CompletersCompleters - 0.7 - 0.7 0.3 0.3p=0.005p=0.005

2.42.4

2.62.6

2.82.8

3.03.0

3.23.2

HOM

A (%

)HO

MA

(%)

2.82.8

3.13.1 3.13.13.03.0

3.13.1

2.62.6

PlaceboPlacebo Rimonabant Rimonabant 20 mg 20 mg

Rimonabant Rimonabant 5 mg 5 mg

Van Gaal et al. Lancet 2005;365:1389-1397Van Gaal et al. Lancet 2005;365:1389-1397

Rimonabant:Rimonabant: Effect on HOMA-derived Effect on HOMA-derived Insulin Resistance (Insulin Resistance (RIO Europe)RIO Europe)

- 60- 60

- 50- 50

- 40- 40

- 30- 30

- 20- 20

- 10- 10

00

- 21%- 21%

- 53%- 53%

p<0.001p<0.001

- 21%- 21%

- 51%- 51%

p<0.001p<0.001

- 39%- 39%

p<0.001p<0.001

- 8%- 8%

Rimonabant: Reduction in Metabolic Rimonabant: Reduction in Metabolic Syndrome (ITT, 1 Year)Syndrome (ITT, 1 Year)

PlaceboPlacebo Rimonabant 20 mgRimonabant 20 mg

Redu

ctio

n (%

)Re

duct

ion

(%)

Van Gaal et al. Lancet 2005;365:1389-1397Van Gaal et al. Lancet 2005;365:1389-1397

Wei

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g)W

eigh

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(kg)

Weight Change at 1 Year is Consistent Across All TrialsWeight Change at 1 Year is Consistent Across All TrialsThe Plateau is a Physiological Phenomenon!The Plateau is a Physiological Phenomenon!

CompletersCompleters

PlaceboPlaceboRimonabant 20 mgRimonabant 20 mg

-10-10

-8-8

-6-6

-4-4

-2-2

00

00 1616 3232 4848

WeeksWeeks



36.2%36.2%

20.2%20.2% 20.6%20.6%

0%0%

20%20%

40%40%27.6%27.6%

15.6%15.6% 16.0%16.0%

0%0%

10%10%

20%20%

30%30%

STRATUS-US TrialSTRATUS-US TrialSmoking abstinence at 7-10 weeksSmoking abstinence at 7-10 weeks Smoking abstinence at end of study Smoking abstinence at end of study

Rimonabant 20 mgRimonabant 20 mgRimonabant 5 mgRimonabant 5 mgPlaceboPlacebo

p < 0.001 for high-dose vs placebop < 0.001 for high-dose vs placebop = NS for low-dose vs placebop = NS for low-dose vs placebo

p < 0.001 for high-dose vs placebop < 0.001 for high-dose vs placebop = NS for low-dose vs placebop = NS for low-dose vs placebo

ACC 2004ACC 2004

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Inhibitors of Membrane Bound Inhibitors of Membrane Bound 5-Lipoxygenase Activating Protein (FLAP)5-Lipoxygenase Activating Protein (FLAP)

FLAPFLAP

Hakonarson et al. JAMA 2005;293:2245-2256Hakonarson et al. JAMA 2005;293:2245-2256

Estimation of Effects of DG-031 on Pts Who Received Estimation of Effects of DG-031 on Pts Who Received the 2 Higher Doses of DG-031 During the First Rx Periodthe 2 Higher Doses of DG-031 During the First Rx Period

Error bars indicate SDs.Error bars indicate SDs.

Carryover Carryover EffectEffect

Carryover Carryover EffectEffect

C-reactive ProteinC-reactive Protein Serum Amyloid ASerum Amyloid A

2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 2 3 4 5 6 7 VisitVisit VisitVisit

Effe

ctEf

fect

0.20.2

00

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-0.2-0.2

-0.4-0.4

-0.6-0.6

-0.8-0.8

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CART-1: Lumen Volume ChangeCART-1: Lumen Volume Change-Reference Segments-Reference Segments

Lum

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mLu

men

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(mm

33 ))IVUS - Non-PCI siteIVUS - Non-PCI site

p = 0.05p = 0.05 AGI 140 mg vs placeboAGI 140 mg vs placebop = 0.09p = 0.09 AGI 280 mg vs placeboAGI 280 mg vs placebop = 0.077 AGI dose-responsep = 0.077 AGI dose-response

Enla

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Narro

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Narro

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Tardif et al. Circulation 2003; 107:552-558Tardif et al. Circulation 2003; 107:552-558

-6-6

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

22

33

44

-5.3-5.3±18.3±18.3

-0.2-0.2±16.9±16.9

-2.4-2.4±17.7±17.7

3.53.5±21.4±21.4

1.81.8±21.3±21.3

PlaceboPlacebo ProbucolProbucol AGI-1067AGI-106770 mg70 mg

AGI-1067AGI-1067140 mg140 mg

AGI-1067AGI-1067280 mg280 mg

(n = 42)(n = 42) (n = 48)(n = 48) (n = 41)(n = 41) (n = 38)(n = 38) (n = 42)(n = 42)

The ARISE Trial: The ARISE Trial: AAggressive ggressive RReduction of eduction of IInflammation nflammation SStops tops EEvents vents

Patients with Patients with CHD as evidenced CHD as evidenced by recent MI/UAby recent MI/UA

> 7 days < 270 days> 7 days < 270 days

Patient population Patient population (N = (N = 66000)000)

DeathDeath Non fatal MINon fatal MI Non fatal StrokeNon fatal Stroke RevascularizationRevascularization Admission for UAAdmission for UA

Primary efficacy Primary efficacy end point:end point:

PlaceboPlacebo

Treatment Treatment (12-24 months)(12-24 months)

AGI-1067 300 mgAGI-1067 300 mg

Steering committee co-chairs: JC Tardif, M PfefferSteering committee co-chairs: JC Tardif, M Pfeffer

Polyphenols: The Case of ResveratrolPolyphenols: The Case of Resveratrol

Resveratrol has been found to exert a Resveratrol has been found to exert a number of potentially cardioprotective number of potentially cardioprotective effects in vitro including:effects in vitro including:

Inhibition of platelet aggregationInhibition of platelet aggregation Promotion of vasodilation by Promotion of vasodilation by enhancing the production of NOenhancing the production of NO Inhibition of inflammatory enzymesInhibition of inflammatory enzymes

Effect of VASOVIN on Human CRP LevelsEffect of VASOVIN on Human CRP Levels

in a h-CRP-transgenic mouse model under basal and interleukin-in a h-CRP-transgenic mouse model under basal and interleukin-66 stimulated conditionsstimulated conditions

40 male mice, 5 groups, 5 weeks.40 male mice, 5 groups, 5 weeks.••Chow diet onlyChow diet only

••Chow diet with 3 increasing VasovinChow diet with 3 increasing Vasovin®® dosages dosages••Chow diet with the anti-inflammatory fenofibrateChow diet with the anti-inflammatory fenofibrate

AIM: Assess anti-inflammatory potency of Vasovin AIM: Assess anti-inflammatory potency of Vasovin ®®by measurement of CRP, Fibrinogen, other inflammatory markersby measurement of CRP, Fibrinogen, other inflammatory markers

Effect of Vasovin Effect of Vasovin on Basal Plasma Fibrinogen Levelson Basal Plasma Fibrinogen Levels

Fibr

inog

en (µ

g/m

L)Fi

brin

ogen

(µg/

mL)

*P<0.05*P<0.05two-sidedtwo-sidedpaired t-testpaired t-test

Con 0.045% 0.15% 0.45% FFCon 0.045% 0.15% 0.45% FF

Plasma FbgnPlasma Fbgnat t=0, 2, 4 wat t=0, 2, 4 w

** **

****

** **

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

A Pill to Prevent 80% of Heart AttacksA Pill to Prevent 80% of Heart Attacks

BMJ 28-06-03BMJ 28-06-03

The Polypill:The Polypill:

Effect of Effect of „Polypill“„Polypill“ on CHD- and Stroke Risk on CHD- and Stroke Risk After 2 Years of Therapy (Age 55-64 Years)After 2 Years of Therapy (Age 55-64 Years)

Wald & Law. BMJ 2003;326:1419-1425Wald & Law. BMJ 2003;326:1419-1425

% Risk Reduction (95% CI)*% Risk Reduction (95% CI)*

Risk FactorRisk Factor CompoundCompound Red. of RFRed. of RF CHD CHD StrokeStroke

LDL-cholesterolLDL-cholesterol Statin †Statin † 1.8 mmol/l 1.8 mmol/l (70mg/dl) LDL-C(70mg/dl) LDL-C 61 (51 to 71)61 (51 to 71) 17 (9 to 25)17 (9 to 25)

Blood pressureBlood pressure 3 compunds with 0.5 3 compunds with 0.5 standard dosestandard dose 11 mm Hg DBP11 mm Hg DBP 46 (39 to 53)46 (39 to 53) 63 (55 to 70)63 (55 to 70)

HomocysteineHomocysteine Folic acid (0.8 mg/d)Folic acid (0.8 mg/d) 3 3 μμmol/lmol/l 16 (11 to 20)16 (11 to 20) 24 (15 to 33)24 (15 to 33)

Platelet functionPlatelet function Aspirin (75 mg/day)Aspirin (75 mg/day) NANA 32 (23 to 40)32 (23 to 40) 16 (7 to 25)16 (7 to 25)

Combined EffectCombined Effect AllAll 88 (84 to 91)88 (84 to 91) 80 (71 to 87)80 (71 to 87)

LDL=low density lipoprotein. †Atorvastatin 10 mg/die, or simvastatin or lovastatin 40 mg/day in the evening LDL=low density lipoprotein. †Atorvastatin 10 mg/die, or simvastatin or lovastatin 40 mg/day in the evening or 80 mg/day in the morning.or 80 mg/day in the morning.

How Much Interest in Polypills?How Much Interest in Polypills?

Increasing interest in preventive medicine and multiple / global Increasing interest in preventive medicine and multiple / global RF assessment / treatment – vs. tailored therapy based on RF assessment / treatment – vs. tailored therapy based on genetic profilegenetic profile

Wald and Law: One in three people would directly benefit, Wald and Law: One in three people would directly benefit, each on average gaining 11-12 years of life without heart each on average gaining 11-12 years of life without heart attack or stroke. attack or stroke.

CNN web poll (based on the above): 95% would take a polypillCNN web poll (based on the above): 95% would take a polypill Google search: poly pill(s) + polypill (s) > 55,000 hitsGoogle search: poly pill(s) + polypill (s) > 55,000 hits Patents: 130?Patents: 130?

In Favor of PolypillsIn Favor of Polypills AdherenceAdherence Pharma and IP holders – new product, market expansion, Pharma and IP holders – new product, market expansion,

commercial advantage over competitors for same indication(s)commercial advantage over competitors for same indication(s) Reduced need for MD contact and follow up; reduced need for Reduced need for MD contact and follow up; reduced need for

screening and confirmatory tests; new care locations (health club, screening and confirmatory tests; new care locations (health club, Pharmacist, self Rx)Pharmacist, self Rx)

CostCost• US and EU pharmacy cost-containment US and EU pharmacy cost-containment • Developing CountriesDeveloping Countries

Potential for improved outcomes. Actual …?Potential for improved outcomes. Actual …? NewsworthinessNewsworthiness

Against - How Many Polypills Could There Be?Against - How Many Polypills Could There Be?

By US pharmacopeia, for CHD prevention alone:By US pharmacopeia, for CHD prevention alone: Perm any combination of 1 of 6 statins, 1 of 10 ACEis, 1 Perm any combination of 1 of 6 statins, 1 of 10 ACEis, 1

of 7 thiazides, 1 of 9 beta-blockersof 7 thiazides, 1 of 9 beta-blockers• = 3780 combinations= 3780 combinations

1 of 7 ARBs, 1 of 10 CCBs, 1 of 10 other BP meds, a 1 of 7 ARBs, 1 of 10 CCBs, 1 of 10 other BP meds, a folic acid, an ASA.folic acid, an ASA.

Dose ranges for some componentsDose ranges for some components ? Add others e.g fibrate, niacin, CETPi, TZD, COX-2 or ? Add others e.g fibrate, niacin, CETPi, TZD, COX-2 or

other anti-inflammatory, cpds in developmentother anti-inflammatory, cpds in development ? Add OTC / other ‘natural’ products? Add OTC / other ‘natural’ products

Designing a PolypillDesigning a Polypill Commercially viable clinical indicationCommercially viable clinical indication Existing components with known characteristics Existing components with known characteristics Pharmaceutically stable when compoundedPharmaceutically stable when compounded PalatablePalatable Same dosing / comparable and compatible kinetics Same dosing / comparable and compatible kinetics

(e.g. qd vs bid, qam vs qhs, food effects, etc) (e.g. qd vs bid, qam vs qhs, food effects, etc) Predictable interactions: probability ~exponentially Predictable interactions: probability ~exponentially

related to # of drugsrelated to # of drugs Predictable AE profilePredictable AE profile

ChallengesChallenges Primum non nocere Primum non nocere – e.g. Lovastatin 10mg (EC), ½ strength BP meds – e.g. Lovastatin 10mg (EC), ½ strength BP meds

– overlap with same OTC argument– overlap with same OTC argument Who will educate pts and monitor, evaluate, report AEs?Who will educate pts and monitor, evaluate, report AEs? Limited pharma interest – competition, low margin (blockbuster Limited pharma interest – competition, low margin (blockbuster

unlikely), erratic use, poaching existing Rx market. So who will unlikely), erratic use, poaching existing Rx market. So who will develop, market, regulate? develop, market, regulate?

Importation, counterfeiting, internet sales – FDA already can’t Importation, counterfeiting, internet sales – FDA already can’t effectively regulate. Could further compromise US prescription and effectively regulate. Could further compromise US prescription and OTC markets.OTC markets.

Who will regulate the explosion of DTC advertising, and false claims Who will regulate the explosion of DTC advertising, and false claims (esp. for OTCs?)(esp. for OTCs?)

Who will conduct and report outcomes and pharmacoeconomic Who will conduct and report outcomes and pharmacoeconomic studies? Will they be done? studies? Will they be done?

Will future studies be obliged to include a Polypill Will future studies be obliged to include a Polypill du jourdu jour as active as active control?control?

Cardiovascular Drugs To WatchCardiovascular Drugs To




Watch

koenig aeha2005 short

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