CURRENT TRENDS IN HYPERTENSION THERAPY

Presented ByPOOJA SHARMA (M. Pharm Pharmacology)

Disease overview

• Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated.

• This requires the heart to work harder than normal to circulate blood through the blood vessels.

The Truth is

It is only a marker of the bigger problem

Hypertension is a multi-organ systemic disease

What we record as B.P.

The Problem is

Hypertension is asymptomatic in 85% of cases

What three factors contribute

to blood pressure?

Epidemiology

Hypertension: the world’s number 1 CV risk factor

• 7.6 million premature deaths worldwide

• 13.5% of global total deaths

• Causes more deaths than any other risk factor, including smoking or high cholesterol

Hypertension is the most powerful risk factor for cardiovascular morbidity and mortality

Global burden of disease

16 million

7–8 million

4–3 million

2–3 million

Global mortality

128 million

59 million

39 million

30 million

All cardiovascular

High BP

High cholesterol

Overweight and obesity

Ezzati et al. PloS Med 2005;2:e133

Hypertension is a leading cause of death and disability in all regions

Region Death Disability*

East Asia & Pacific 13.6% 6.5%

Europe & Central Asia 35.0% 19.6%

Latin America & The Caribbean 13.0% 5.1%

Middle East & North Africa 16.5% 6.1%

South Asia 9.6% 4.3%

Sub-Saharan Africa 4.0% 1.7%

Low-/ middle-income economies 12.9% 5.6%

High-income economies 17.6% 9.3%

World 13.5% 6.0%

Lawes et al. Lancet 2008;371:1513–8

BP is often not controlled, even when treated

0

10

20

30

40

50

60

70

80

Aware Treated Controlled

USACanadaItalySwedenSpainEnglandGermany

Wolf-Maier et al. Hypertension 2004;43:10–17* Threshold of SBP/DBP 140/90 mm Hg

Each 20/10 mm Hg BP increase doubles the risk of CV mortality

1-fold

2-fold

4-fold

8-fold

0

2

4

6

8

10

SBP/DBP, mm Hg

* Individuals aged 40–69 years (N = 1 million).Lewington S, et al. Lancet. 2002;360:1903–1913.

Hypertension adds to other CV risk factors

Other risk factors

SBP 120–129DBP 80–84

SBP 130–139DBP 85–89

SBP 140–159DBP 90–99

SBP 160–179DBP 100–109

SBP ≥180DBP ≥110

NoneAverage

riskAverage

riskLow

added riskModerate added risk

High added risk

1−2Low

added riskLow added

riskModerate added risk

Moderate added risk

Very high added risk

≥3, OD, MS or diabetes

Moderate added risk

High added risk

High added risk

High added risk

Very high added risk

CV or renal disease

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

MS, metabolic syndrome; OD, subclinical organ damage

ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187

Treatment goals and algorithms

Treatment Goal

The Truth is

Keep B.P. < 140/90 mm Hg in each patient

This may be revised to 120/80 may be ? 110/70

It is essential to keep the B.P at or below the goal

But, It also matters how the goal B.P. is achieved !

Goal BP

Current BP targets according to guidelines

JNC VII 2003 ESH-ESC 2007 WHO-ISH BHS IV 2006

<140/90* <140/90 SBP <140 <140/90

<130/80 <130/80 <130/80 According to national

guidelines

DM renal

DMrenal

post strokepost MI

DMrenalCVD

DMrenal CVD

* Lower if tolerated

Blood Pressure Classification

Seventh Joint USA National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure -JNC 7, JAMA, May 21, 2003, and USA Government Printing Office publication.

Hypertension treatment algorithm (JNC 7)

Hypertension treatment algorithm (ESH 2007)

Choose between

Low-dose 2-drug combinationLow-dose single agentNot at BP goal

Full dose ofsingle agent

Switch todifferent agent

at low dose

Full dose of2-drug

combination

Add athird drug

at low dose

Not at BP goal2–3 drugcombinationat full dose

Full doses of 2–3-drugcombination

Full-dosesingle agent

Marked BP elevationHigh/very high CV risk

Lower BP target

Mild BP elevationLow/moderate CV risk

Conventional BP target

ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187

Approaching Hypertension

Pharmacologic treatment

Diuretics

Beta blockers

CCBs

ARBs

ACE – inhibitors

Enalapril

Lisinopril

Ramipril

Quinapril

Perindopril

Hypertension

Centrally acting agents

The Many Faces of HT Therapy Today

• Guidelines on the choice of agents and how best to step up treatment for various subgroups have changed over time and differ between countries.

• The best first line agent is disputed. The Cochrane collaboration, WHO and the US guidelines supports low dose thiazide-based diuretic as first line treatment.

• The UK guidelines emphasize calcium channel blockers in preference for people over the age of 55 years or if of African or Caribbean family origin, with angiotensin converting enzyme inhibitors used first line for younger people. In Japan starting with any one of six classes of medications including: CCB, ACEI/ARB, thiazide diuretics, beta-blockers, and alpha-blockers is deemed reasonable while in Canada all of these but alpha-blockers are recommended as options.

AGE

Younger (< 55)High Renin HT

Renin

ACEi, Beta-blocker Ca++-blocker, Diuretic)(AB/CD=

Dickerson et al. Lancet 353:2008-11;1999

Older (> 55)Low Renin HT

ACEi BB

A + B A + B + D

DiureticCCB

D + C + A D + C

I

II

III III

II

I

AB/CD Rule – HT Treatment

Each of the main classes of anti-hypertensive drugs affects the renin-angiotensin system

Brown. Heart 2007;93:1026–33

DiureticCalcium

channel

blocker

ACE inhibitor

Angiotensin receptorblocker

Beta-blockers

Kidney

ACE

Angiotensin I

Angiotensin II

AT1 receptor

Arteries – vascular tone

Na+

Renin

Angiotensinogen

++

ReninVolume

–

–

–

–

Bradykinin/NO

Inactive fragments

Angiotensin I

Angiotensin II

ACEI and ARBs block the renin-angiotensin system (RAS) in different ways

ARB

ACE-independentANG II formation by Chymase, etc.

AT2 RECEPTORVasodilationNatriuresis

Tissue regenerationInhibition of inappropriate cell growth

DifferentiationAnti-inflammation

Apoptosis

ACE ACE Inhibitor

AT1 RECEPTOR

VasoconstrictionSodium retention

SNS activationInflammation

Growth-promoting effectsAldosteroneApoptosis

SNS = sympathetic nervous systemHanon S, et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R, et al. Hypertension 2003;42:542–547; Hurairah H, et al. Int J Clin Pract 2004;58:173–183;Steckelings UM, et al. Peptides 2005;26:1401–1409

DIURETICSFirst and Best Choice

Can be combined with A, B, C

βBlockersGood third Choice

Can be combined with A, D

Ca channel BlockersFourth Choice, Useful

Can be combined with D, A

ACEI and ARBSecond Best Choice

Can be combined with D, B, C

D

Diuretics

A

ACEI, ARB

B

β-Blockers

C

Ca-Blockers

D A

B C

The A B C D classes

KNOW ME WELL

I am ‘D’ for DIURETIC My Good aspects

Fluid depletion, Na washout, Low costImprove CHF, Systolic function, Ca savingReduce LVH, Morbidity & Mortality

My Bad aspectsPotassium washout, ↑ in Uric acid, ↑ CaAdverse on Lipids, Glucose control

Don’t use me inGout, HypokalaemiaDyslipedemia, Uncontrolled DM

DIURETIC

Diuretics help the kidneys eliminate excess salt and water from the body's tissues and blood.Loop diuretics:

Bumetanide, ethacrynic acid, furosemide, torsemide.

Thiazide diuretics:Epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide

Thiazide-like diuretics:Indapamide, chlorthalidone, metolazone.

Potassium-sparing diuretics:Amiloride, triamterene, spironolactone

Only the thiazide and thiazide-like diuretics have good evidence of beneficial effects on important endpoints of hypertension, and hence, should usually be the first choice when selecting a diuretic to treat hypertension. The reason why thiazide-type diuretics are better than the others is (at least in part) thought to be because of their vasodilating properties.

KNOW ME WELL

I am ‘A’ for ACEI and ARB My Good aspects

Improve Diastolic function, Systolic functionControl Proteinuria, Very favourable in DMImprove Coronary Ischemia, Good on

Lipids Reduce LVH, Morbidity & Mortality

My Bad aspectsBradykinin accumulation, Angio-edema↑ Serum K , ↓ GFR

Don’t use me inPregnancy, Creatinine is > 3 mg%, ↑ K

5.0 meqBilateral Renal Artery Stenosis, Angio-

edema

ACE inhibitors can be divided into three groups based on their molecular structure:

Sulfhydryl-containing agentsCaptopril , the first ACE inhibitorZofenopril

Dicarboxylate-containing agentsThis is the largest group, including:EnalaprilRamiprilQuinaprilPerindoprilLisinoprilBenazeprilImidaprilZofenoprilTrandolapril

Phosphonate-containing agentsFosinopril is the only member of this group

Angiotensin II receptor antagonists

Pressor inhibition at trough level - this relates to the degree of blockade or inhibition of the blood pressure-raising effect of angiotensin II.

However, pressor inhibition is not a measure of blood pressure-lowering (BP) efficacy per se.

The rates as listed in the US FDA Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)

Valsartan 80 mg 30%Telmisartan 80 mg 40%Losartan 100 mg 25–40%Irbesartan 150 mg 40%Irbesartan 300 mg 60%Azilsartan 32 mg 60%Olmesartan 20 mg 61%Olmesartan 40 mg 74%

I am ‘B’ for βBlocker

My Good aspects ↓Heart rate, ↓Force of contraction, ↓Conduction ↓Myocardial O2 demand, Improve Ischemia

Improve QUALY in CHD, Useful in CHF, Migraine My Bad aspects

Constrict peripheral vessels, BradycardiaUnfavourable on Lipids, Glucose

Don’t use me inBradycardia, Conduction defects, Caution in CHFPrinzmetal Angina, MSD, PVD, BA, COPD, Dys

lipidPheochromocytoma, Chronic smokers

β Blocker KNOW ME WELL

Nonselective agentsAlprenolol, Bucindolol, Carteolol, Carvedilol (has additional α-blocking activity)Labetalol (has additional α-blocking activity), Nadolol, Oxprenolol (has intrinsic sympathomimetic activity), Penbutolol (has intrinsic sympathomimetic activity)

β1-selective agentsAlso known as cardioselectiveBetaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol (also increases nitric oxide release for vasodilation)

β2-selective agentsButaxamine (weak α-adrenergic agonist activity): No common clinical applications, but used in experiments.ICI-118,551: Highly selective β2-adrenergic receptor antagonist—no known clinical applications, but used in experiments due to its strong receptor specificity.

β3-selective agentsSR 59230A (has additional α-blocking activity): Used in experiments.

KNOW ME WELL

I am ‘C’ for Ca channel Blocker

My Good aspectsVasodilatory, Suitable in elderly, Low costAnti arrhythmic (Verapamil), ↑Coronary BF (Diltz)Neutral on lipidemia, Vasospastic Angina

My Bad aspectsFluid retention, Impair failing heartAdverse on Glucose control.

Don’t use me inTachycardia, arrhythmias, CHF, Uncontrolled DM, Volume overload

• Dihydropyridine CCBs are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina because the vasodilation and hypotension can lead to reflex tachycardia.

Amlodipine, Aranidipine, Azelnidipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, Isradipine, Efonidipine, Felodipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Manidipine, Nicardipine,Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine.

• Phenylalkylamine CCBs are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina.

Verapamil • Benzothiazepine CCBs by having both cardiac depressant and

vasodilator actions, are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation.

Diltiazem (Cardizem)• Nonselective mibefradil, bepridil, fluspirilene, and fendiline.

RENIN INHIBITORS• These drugs inhibit the first and rate-limiting step of the renin-

angiotensinaldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I.

• Aliskiren is effective in lowering blood pressure, but as of 20 April 2012 the US Food and Drug Administration (FDA) issued a warning of possible risks when using aliskiren or blood pressure medicines containing aliskiren with ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or kidney (renal) impairment. They advised that such drug combinations should not be used in patients with diabetes because of the risk of causing renal impairment, hypotension, and hyperkalemia and that aliskiren should not be used with ARBs or ACE inhibitors in patients with moderate to severe renal impairment. However, they also recommend that patients should not stop taking aliskiren without talking to a healthcare professional.

• Aliskiren in combination with hydrochlorothiazide was approved by the FDA in 2008

The importance of treatment adherence

Patients who are adherent are more likely to attain BP control

Controlled BP (%)

* <140/90 mmHg or <130/85 mmHg for patients with diabetes

Bramley et al. J Manag Care Pharm 2006;12:239–45

0

5

10

15

20

25

30

35

40

45

50

Low (<50%) Medium (50-79%) High (>=80%)

45% greater probability of control

Adherence(n = 165)(n = 46) (n = 629)

Treatment adherence is highest with ARBs

ARB, angiotensin II receptor blocker; CI, confidence interval* Relative to ACE inhibitors after 1 year of treatment

Corrrao et al. J Hypertens 2008;26:819-24.

0.5 1.0 2.0

Diuretics

β-blockers

α-blockers

Calcium channel blockers

ACE inhibitors

ARBs

1.83

1.64

1.23

1.08

1.00

0.92

- +Cause-specific hazard ratio (95% CI) for discontinuation*

Total n = 445,356

Persistence with hypertensive therapy

Monotherapy or combination treatment for hypertension

• Antihypertensive monotherapy is effective in only

about 40-60% of hypertensive patients, irrespective of

the category of the agent that is used.

• Most of the responders are Stage I hypertensives.

Therefore, there is frequently a need for the use of

two medications with different mechanisms of action.

• Should therapy be started with two drugs or a

combination?

Monotherapy

Average no. of antihypertensive medications

1 2 3 4

Trial (SBP achieved)

ASCOT-BPLA (136.9 mmHg)

ALLHAT (138 mmHg)

IDNT (138 mmHg)

RENAAL (141 mmHg)

UKPDS (144 mmHg)

ABCD (132 mmHg)

MDRD (132 mmHg)

HOT (138 mmHg)

AASK (128 mmHg)

The majority of hypertensive patients need combination therapy to achieve their BP target (SBP)

Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906

Hypertension – Why Combinations ? If goal BP is not achieved by a single drug in full

dose

Then adding another agent will help achieve the goal BP

Two agents sometimes nullify each others side effects

Fixed dose combinations will reduce the no. of tablets

Once daily formulations are good for compliance

Sustained release or Long Acting formulations for 24 h BP control

If three drugs can’t achieve goal BP – Resistant HT

Diuretics

β-blockers

α-blockers

ACEi

CCB

ARB

Adapted from Mancia et al. J Hypertens 2007;25:1105–87Manchia et al J Hypertens 2009; 27: 2121-58

Diuretics

ACEi

CCB

ARBONTARGETACCOMPLISHHYVET

2007

2009

ESH-ESC treatment recommendations

Drug Combinations

Hypertension – Rational Drug Combinations

ACEI and ARB = A

Beta Blockers = B

Calcium Channel (CCB) = C

Diuretics Drugs= D

D and A combination is excellent - Ramace H, Losar H, Enace D

D and B combination second - Betaloc H, Atecard D, Tenoric

D and C combination sixth - Amlogaurd H, Stamlo D

A and B combination Third - Losar A, Cardif Beta

A and C combination fourth - Amlopres L, Hipril A, Amlo LS

B and C combination fifth - Amlo AT, Amlobet, Beta Nicardia

Diuretics = D – Rank 1

ACEI and ARB = A – Rank 2

Beta Blockers = B – Rank 3

CCB = C – Rank 4

Some Irrational Combinations

Beta blockers + Beta1 stimulants - Rebound HT, Paradoxical BP ↑

Beta blockers + Vepapamil - Extreme bradycardia, HB, CHF

Thiazide + Furesemide - Potential volume ↓ and K ↓

CCB + Thiazide- No RCTs to support the additive

Prazocin + Beta blocker - They nullify the effects of each other

Verapamil / Dilzem + Nefidepine -No rationale (cardiac actions contridic)

Beta blocker + ACEI Not for HT alone, Good for CHF, MI, IHD

Sub clinical doses of two drugs Try one drug in good dosage, then add

Two drugs of same class - No rationale (like Enalapril + Ramipril)

(Atenelol + Metoprolol, Nefidepine + Amlo)

Incidence of New Onset Diabetes with Various Medications.

How significant is it?

Risk of Hyperglycemia with Use ofAntihypertensive Drugs

Thiazide

Central antiadrenergic agents

Peripheral antiadrenergic agents

ACE inhibitors

B-Blockers

Calcium channel blockers

Vasodilators

>1 Agent without thiazide

>1 Agent with thiazide0.5 1 1.5 2 2.5 3

DecreasedRisk

IncreasedRisk

Adjusted ORs and 95% CIGurwitz J H. Arch Intern Med 1993;118:273-278

DecreasedRisk

IncreasedRisk

Ongoing trends

Review of companies and drug classes in the 2007–2011 antihypertensive patent literature

Future treatment options

Orally Active Aminopeptidase A Inhibitor -- a

Prototype for a New Antihypertensive Drug Class

• RB150, an orally active prodrug that inhibits brain but not

systemic renin-angiotensin system (RAS) activity, reducing

blood pressure in an experimental animal model, is reported.

• Previous research indicated that in the brain, conversion of

Ang II to Ang III, which is catalyzed by aminopeptidase A

(APA), is a necessary step in increasing blood pressure. They

used specific and selective APA inhibitors to show that Ang III

is one of the main effector peptides of the brain RAS ,

exerting tonic stimulatory control over BP in hypertensive

rats. APA, therefore, is a potential therapeutic target for the

treatment of hypertension.

Identification of Angiotensin-Converting Enzyme-2

Activators as Potential Antihypertensive Drugs

• ACE 2, a homolog of ACE, is a key RAS enzyme involved in

balancing the adverse effects of angiotensin II on the

cardiovascular system. It is known to degrade angiotensin II

(Ang II) to generate angiotension which has vasodilatory and

antiproliferative effects. Blocking AngII with ACE inhibitors or

angiotensin receptor blockers (ARBs) has been shown to

increase cardiac ACE 2 expression.

• Altered expression of ACE 2 is associated with cardiac, renal,

and vascular dysfunction.

Slow-Releasing Hydrogen Sulfide Compound With Potential as Antihypertensive Therapy

• Hydrogen sulfide (H2S) is known to have cardiovascular effects such as the ability to dilate human blood vessels and protect the heart against ischemia/perfusion injury, and it also plays a role in hypertension.

• Researchers have identified a slow-releasing H2S compound that mimics the generation of H2S in vivo.

• In addition, the blood pressure lowering effect of the compound is without affecting heart rate and withoutweight loss or other signs of toxicity, suggests that it, or a compound like it, may be of a therapeutic benefit in cardiovascular disease.

• The compound GYY4137 was found to release H2S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo.

• It caused a slow relaxation of precontracted rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle adenosine triphosphate-sensitive potassium (KATP) channels.

• Aliskiren is a novel, completely nonpeptide, orally active renin inhibitor that blocks the first and rate-limiting step of the renin-angiotensin system.

• Alagebrium, an advanced glycation end product (AGE) crosslink breaker, has been shown to reduce SBP in patients with uncontrolled systolic hypertension.

• Progestin drospirenone and 17 beta-estradiol (DRSP/E2), developed for postmenopausal hormone replacement therapy, has been shown to lower both clinic and ambulatory SBP in postmenopausal women .

Antihypertensives Market to 2016 - Generic Erosion Following Patent Expiry of Major ARBs to Impact the Market

The global market:

overview, opportunities and threats

The Global Anti-Hypertensive Market is Set to Show Flat Growth in the near Future

In 2009, the global anti-hypertensive market was estimated to be worth $27.2 billion, representing a Compound Annual Growth Rate (CAGR) of 5.0% between 2002 and 2009. The market is forecast to reach $30 billion by 2016, indicating a CAGR of 1.5% between 2009 and 2016. The primary reason for slight and gradual growth in the market is the patent expiries of major blockbusters, which are expected to decrease the annual cost of therapy after 2007.

The global anti-hypertensive market is expected to witness a series of patent expiries between 2007 and 2015, which includes most of the top selling blockbuster drugs in the anti-hypertensive market. The major drugs that are set to lose patent protection include Novartis’s Diovan (2012), Sanofi Aventis’s Avapro (2012), Novartis’s Exforge (2012), Takeda/AstraZeneca’s Blopress/Atacand (2012), Pfizer’s Revatio (2012), Actelion’s Tracleer (2015), and United Therapeutics Remodulin (2014).

All these drugs together accounted for more than $19.4 billion in revenues in 2009. Merck’s Cozaar patent expired in April 2010. The sales of Cozaar for the year 2009 were $3.6 billion. Pfizer’s Norvasc, which was once the world’s most prescribed drug for hypertension and angina, saw a sales decline of 12% in 2009 due to genericization in 2007. Thus, the series of upcoming patent expiries in the hypertension as well as PAH markets are set to lead to a decline in the market in the near future. However, due to increased usage of fixed dose-combinations and the entry of generics, the market is expected to rise slightly after 2015.

The current anti-hypertensive pipeline does offer some promising novel products, such as SPP635, Actos, LCZ696, QT1571, ACT-293987, PS-433540, Macitentan and Riociguat, indicated for the treatment of hypertension and PAH. However, the revenues generated from these products are not expected to completely make up for the revenue losses due to patent expiries. Thus, the overall global anti-hypertensive market is expected to show flat growth during the forecast period.

Top Six Companies Control Approximately 74% of the Market

The current global anti-hypertensive market is significantly consolidated as the top six players control approximately 74% of the market. Novartis is the current market leader with its blockbuster product, Diovan. It is available in more than 100 countries. It has recorded sales of six billion in 2009. Other major products in the anti-hypertensive market of Novartis are Exforge, Tekturna/Rasilez, Lotrel and Lescol, controlling 43% of the total anti-hypertensive market. Merck follows Novartis with a 19% market share, primarily due to its top selling ARB, Cozaar. The sales of Cozaar are set to decline in the future as the patent on Cozaar expired in April 2010. Pfizer occupies the third position with its blockbuster drug Norvasc. Pfizer also marks its presence in the PAH market with its Revatio. Norvasc went off-patent in the year 2007. It was one of the blockbuster drugs in the anti-hypertensive market until this date. Takeda is the fourth player in the anti-hypertensive market, with its blockbuster drug Blopress.

The sales of Blopress are set to increase in the coming years. Takeda is followed by Actelion and Sanofi Aventis. Actelion is the market leader in PAH with its blockbuster drugs, Tracleer and Ventavis. Actelion and Sanofi Aventis control 8% and 7% of the total market. However, the market shares of the total players are expected to witness changes in the near future due to upcoming patent expiries. Novartis’s Diovan and Tekturna/Rasilez are set to expire in 2012. Exforge is set to expire in 2010. Merck’s Cozaar went off-patent in the year 2010. Merck and Pfizer have been registering negative growth in recent years due to patent expiries. Novartis, Takeda and Actelion have shown positive growth.

• The growth rate of the antihypertensive market is declining. These changes reflect the challenges faced by pharmaceutical companies over the next decade, as brand erosion and healthcare reforms impact heavily.

• The slow and declining growth rate does not reflect a stationary market, but the battle between the drugs that make up the market.

We are still evolving towards finding an Ideal Antihypertensive