Basics of hypertension and available treatment. Overview of mechanism of action, risks/benefits of various classes of drugs. Prevalent prescription trends and future market review.

1. CURRENT TRENDS IN HYPERTENSION THERAPY
Presented By
POOJA SHARMA
(M. Pharm Pharmacology)

2. 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.

3. 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

4. What three factors contribute
to blood pressure?

7. Epidemiology

8. 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

9. 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

10. 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

11. BP is often not controlled, even when
treated
0
10
20
30
40
50
60
70
80
Aware Treated Controlled
USA
Canada
Italy
Sweden
Spain
England
Germany
Wolf-Maier et al. Hypertension 2004;43:10–17
* Threshold of SBP/DBP 140/90 mm Hg

12. 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.

13. Hypertension adds to other CV risk factors
Other risk
factors
SBP 120–129
DBP 80–84
SBP 130–139
DBP 85–89
SBP 140–159
DBP 90–99
SBP 160–179
DBP 100–109
SBP ≥180
DBP ≥110
None
Average
risk
Average
risk
Low
added risk
Moderate
added risk
High
added risk
1−2
Low
added risk
Low added
risk
Moderate
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

14. Treatment goals and algorithms

15. 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

16. 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
DM
renal
post stroke
post MI
DM
renal
CVD
DM
renal
CVD
* Lower if tolerated

17. 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.

18. Hypertension treatment algorithm (JNC 7)

19. Hypertension treatment algorithm
(ESH 2007)
Choose between
Low-dose 2-drug combinationLow-dose single agent
Not at BP goal
Full dose of
single agent
Switch to
different agent
at low dose
Full dose of
2-drug
combination
Add a
third drug
at low dose
Not at BP goal2–3 drug
combination
at full dose
Full doses of 2–3-drug
combination
Full-dose
single agent
Marked BP elevation
High/very high CV risk
Lower BP target
Mild BP elevation
Low/moderate CV risk
Conventional BP target
ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187

20. Approaching Hypertension
Pharmacologic treatment

21. Enalapril
Lisinopril
Ramipril
Quinapril
Perindopril
Hypertension
The Many Faces of HT Therapy Today

22. • 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.

25. 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

26. Each of the main classes of anti-hypertensive
drugs affects the renin-angiotensin system
Brown. Heart 2007;93:1026–33
Diuretic
Calcium
channel
blocker
ACE inhibitor
Angiotensin receptor
blocker
Beta-blockers
Kidney
ACE
Angiotensin I
Angiotensin II
AT1 receptor
Arteries – vascular tone
Na+
Renin
Angiotensinogen
++
Renin
Volume
–
–
–
–

27. Bradykinin/NO
Inactive fragments
Angiotensin I
Angiotensin II
ACEI and ARBs block the renin-angiotensin
system (RAS) in different ways
ARB
ACE-independent
ANG II formation
by Chymase, etc.
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
ACEACE
Inhibitor
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
SNS = sympathetic nervous system
Hanon 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

28. DIURETICS
First and Best Choice
Can be combined with A, B, C
βBlockers
Good third Choice
Can be combined with A, D
Ca channel Blockers
Fourth Choice, Useful
Can be combined with D, A
ACEI and ARB
Second 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

29. KNOW ME WELL
I am ‘D’ for DIURETIC
 My Good aspects
Fluid depletion, Na washout, Low cost
Improve CHF, Systolic function, Ca saving
Reduce LVH, Morbidity & Mortality
 My Bad aspects
Potassium washout, ↑ in Uric acid, ↑ Ca
Adverse on Lipids, Glucose control
 Don’t use me in
Gout, Hypokalaemia
Dyslipedemia, Uncontrolled DM
DIURETIC

30. 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.

31. KNOW ME WELL
I am ‘A’ for ACEI and ARB
 My Good aspects
Improve Diastolic function, Systolic function
Control Proteinuria, Very favourable in DM
Improve Coronary Ischemia, Good on Lipids
Reduce LVH, Morbidity & Mortality
 My Bad aspects
Bradykinin accumulation, Angio-edema
↑ Serum K , ↓ GFR
 Don’t use me in
Pregnancy, Creatinine is > 3 mg%, ↑ K 5.0 meq
Bilateral Renal Artery Stenosis, Angio-edema

32. ACE inhibitors can be divided into three groups based on
their molecular structure:
Sulfhydryl-containing agents
Captopril , the first ACE inhibitor
Zofenopril
Dicarboxylate-containing agents
This is the largest group, including:
Enalapril
Ramipril
Quinapril
Perindopril
Lisinopril
Benazepril
Imidapril
Zofenopril
Trandolapril
Phosphonate-containing agents
Fosinopril is the only member of this group

33. 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%

34. 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, Bradycardia
Unfavourable on Lipids, Glucose
 Don’t use me in
Bradycardia, Conduction defects, Caution in CHF
Prinzmetal Angina, MSD, PVD, BA, COPD, Dys lipid
Pheochromocytoma, Chronic smokers
β Blocker KNOW ME WELL

35. Nonselective agents
Alprenolol, 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 agents
Also known as cardioselective
Betaxolol, Bisoprolol, Celiprolol, Esmolol, Metoprolol, Nebivolol
(also increases nitric oxide release for vasodilation)
β2-selective agents
Butaxamine (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 agents
SR 59230A (has additional α-blocking activity): Used in experiments.

36. KNOW ME WELL
I am ‘C’ for Ca channel Blocker
 My Good aspects
Vasodilatory, Suitable in elderly, Low cost
Anti arrhythmic (Verapamil), ↑Coronary BF (Diltz)
Neutral on lipidemia, Vasospastic Angina
 My Bad aspects
Fluid retention, Impair failing heart
Adverse on Glucose control.
 Don’t use me in
Tachycardia, arrhythmias, CHF,
Uncontrolled DM, Volume overload

37. • 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.

38. 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

39. The importance of
treatment adherence

40. 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)

41. 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

42. Persistence with hypertensive therapy

43. Monotherapy or combination
treatment for hypertension

44. • 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

45. 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

46. 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

47. Diuretics
β-blockers
α-blockers
ACEi
CCB
ARB
Adapted from Mancia et al. J Hypertens 2007;25:1105–87
Manchia et al J Hypertens 2009; 27: 2121-58
Diuretics
ACEi
CCB
ARBONTARGET
ACCOMPLISH
HYVET
2007 2009
ESH-ESC treatment recommendations

48. Drug Combinations

49. 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

50. 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)

51. Incidence of New Onset Diabetes
with Various Medications.
How significant is it?

52. Risk of Hyperglycemia with Use of
Antihypertensive Drugs
Thiazide
Central antiadrenergic agents
Peripheral antiadrenergic agents
ACE inhibitors
B-Blockers
Calcium channel blockers
Vasodilators
>1 Agent without thiazide
>1 Agent with thiazide
0.5 1 1.5 2 2.5 3
Decreased
Risk
Increased
Risk
Adjusted ORs and 95% CI
Gurwitz J H. Arch Intern Med 1993;118:273-278
Decreased
Risk
Increased
Risk

53. Ongoing trends
Review of companies and drug
classes in the 2007–2011
antihypertensive patent literature

57. Future treatment options

59. 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.

60. 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.

61. 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 without
weight loss or other signs of toxicity, suggests that it, or
a compound like it, may be of a therapeutic benefit in
cardiovascular disease.

62. • 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.

63. • 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 .

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

65. The global market:
overview, opportunities and threats

66. 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).

67. 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.

68. 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.

69. 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.

70. • 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.

71. We are still evolving towards finding an
Ideal Antihypertensive