Cardiac Market Outlook - 2016 by Nitesh bhele

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The Cardiovascular Market Outlook
to 2016
Competitive landscape, global market analysis, key trends, and pipeline
analysis
Reference Code: BI00042-007
Publication Date: June 2011

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About Business Insights
Business Insights has a team of in-house pharmaceutical and regulatory analysts drawn from consulting,
R&D and competitive intelligence life sciences backgrounds. Our analysts specialize in providing detailed
insight into the future of therapeutic drug markets and emerging pharmaceutical markets and have extensive
analytical, forecasting and research experience in the pharmaceutical, biotech and outsourcing sectors. Our
team maintains regular contact with industry executives to track market developments and base their market
models on a wide range of proprietary drug sales, pipeline and epidemiological databases to provide up to
date, accurate strategic insight on the future of the pharmaceutical market.
Disclaimer
Copyright © 2011 Business Insights Ltd
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opinions and do not necessarily reflect the views/opinions of the Publisher.

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Table of Contents
About Business Insights 2
Disclaimer 2
Executive Summary 13
Overview and epidemiology of cardiovascular disorders 13
Global market analysis 13
Pipeline analysis 14
Competitive landscape 15
Chapter 1 Overview and epidemiology of cardiovascular disorders 17
Summary 17
Introduction 17
Risk factors 18
Predisposing risk factors 18
Modifiable risk factors 21
Hypertension 21
Diagnosis, treatment and management 22
Epidemiology 24
Forecast epidemiology 26
Dyslipidemia 27
Diagnosis, treatment, and management 29
Epidemiology 30
Cardiovascular diseases 33
Arteriosclerosis/atherosclerosis 33

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Thrombosis 33
Cardiac arrhythmias 33
Myocardial infarction (MI) 33
Acute coronary syndrome (ACS) 34
Congestive heart failure (CHF) 34
Coronary artery disease (CAD) 34
Peripheral artery disease (PAD) 34
Pulmonary hypertension 34
Angina pectoris 35
Stroke 35
Epidemiology 35
Chapter 2 Global market analysis 38
Summary 38
Introduction 39
Market analysis by geography 40
Key events in the cardiovascular market 41
European approval for Rasilamlo 41
BMS/Pfizer’s apixaban likely to receive EU approval 41
Angiotensin receptor blockers (ARBs) may cause increased cancer risk 42
Crestor’s patent upheld in the US 43
Plavix boxed warning for poor metabolizers 43
Market analysis by drug class 44
Antihypertensives 46
Introduction 46
Antihypertensive drug classes 46
Leading treatment brands by drug class 47

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Key brands analysis 51
Diovan/Co-Diovan 51
Cozaar 51
Benicar 53
Antidyslipidemics 54
Introduction 54
Antidyslipidemic drug classes 54
Lipitor 57
Crestor 59
Future blockbusters in the antidyslipidemic drug class 63
Antithrombotics 65
Introduction 65
Antithrombotics drug classes 66
Plavix 68
Lovenox 71
Future blockbusters in the antithrombotic drug class 72
Other cardiovascular agents 75
Introduction 75
Tracleer 77
Leading brands dynamics and sales forecasts 78
Product growth-share matrix for leading brands 78
Chapter 3 Pipeline analysis 81
Summary 81

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Introduction 82
Key events in the cardiovascular market 82
First advanced therapy certificate for t2cure’s somatic cell therapy 82
Clear evidence of safety leads to termination of apixaban’s Phase III AVERROES trial 83
FDA panel to review AstraZeneca’s Brilinta 83
Novartis presents successful Phase II results of LCZ696 84
Daiichi Sankyo’s CS-8635 shows promising results in pivotal trial 84
Sanofi (Genzyme)/Isis’ mipomersen clears second Phase III trial, but raises safety concerns 85
Cardiovascular pipeline 85
Leading drugs in development 86
Profiles of key pipeline products 88
Key antihypertensive pipeline drugs 90
LCZ696 – Novartis 90
Cinaciguat – Bayer 92
Riociguat – Bayer 93
Key antidyslipidemic pipeline drugs 95
Livalo (pitavastatin) – Kowa Pharmaceuticals 95
Dalcetrapib – Roche 96
Anacetrapib – Merck 97
Darapladib – GlaxoSmithKline 99
Key antithrombotic pipeline drugs 100
Xarelto (rivaroxaban) – Bayer/J&J 100
Apixaban – Bristol-Myers Squibb (BMS)/Pfizer 102
Brilinta (ticagrelor) – AstraZeneca 104
Betrixaban – Portola/Merck 106
Chapter 4 Competitive landscape 109
Summary 109
Introduction 109
Competitive positioning of top players in the cardiovascular market 110

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Pfizer 111
Overview 111
Marketed product portfolio 112
Lipitor (atorvastatin) 112
Norvasc (amlodipine) 114
Caduet (atorvastatin/amlodipine) 114
Revatio (sildenafil) 115
Fragmin (dalteparin) 115
R&D pipeline analysis 116
Strategic and growth analysis 116
Drivers of growth 116
Resistors of growth 117
Sanofi 118
Overview 118
Lovenox (enoxaparin) 120
Plavix (clopidogrel) 121
AstraZeneca 124
Overview 124
Crestor (rosuvastatin) 126
Atacand (candesartan cilexetil) 127
Novartis 130

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Overview 130
Diovan (valsartan) 131
Exforge (amlodipine/valsartan) 132
Lescol (fluvastatin) 132
Lotrel (amlodipine/benazepril) 133
Bristol-Myers Squibb (BMS) 136
Overview 136
Plavix (clopidogrel) 137
Avalide/Avapro (irbesartan HCT) 138
Coumadin (warfarin) 138
Merck 141
Overview 141
Cozaar/Hyzaar (losartan/losartan HCT) 143
Vytorin (ezetimibe/simvastatin) 143
Appendix 147
Scope and methodology 147

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Scope 147
Methodology 148
Market size methodology 148
Epidemiology 148
Market forecast 148
Abbreviations 149
References 155

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Table of figures
Figure 1: Cardiovascular disease etiology 20
Figure 2: Cardiovascular risk factors and definitions 21
Figure 3: Definition and classification of hypertension 22
Figure 4: Hypertension treatment options 24
Figure 5: Types of lipoproteins 28
Figure 6: Interpretation of blood lipid levels 29
Figure 7: LDL levels and therapy patterns 30
Figure 8: Geographical segmentation of the global cardiovascular market, 2010 and 2016 41
Figure 9: Global market share of major cardiovascular drug classes (%), 2010–16 45
Figure 10: Sales of potential antidyslipidemic drugs versus Lipitor ($m), 2010–16 65
Figure 11: Sales of antithrombotic drugs by disease conditions in the US ($m), 2010–16 73
Figure 12: Forecast market share of antithrombotic drugs under development, 2010–16 75
Figure 13: Leading brands product growth BCG matrix 79
Figure 14: Cardiovascular pipeline by key indications and stages of development, 2010 86
Figure 15: Leading pipeline drugs in various cardiovascular sub-categories, 2010 89
Figure 16: US FDA drug approval activities, 2000–2010 90
Figure 17: Pfizer cardiovascular portfolio by brand (%), 2010 114
Figure 18: Sanofi cardiovascular portfolio by brand (%), 2010 120
Figure 19: AstraZeneca cardiovascular portfolio by brand (%), 2010 125
Figure 20: Novartis cardiovascular portfolio by brand (%), 2010 131
Figure 21: BMS cardiovascular portfolio by brand (%), 2010 137
Figure 22: Merck cardiovascular portfolio by brand (%), 2010 142

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Table of tables
Table 1: Estimated prevalence of cardiovascular disorders across the 7MM, 2010 18
Table 2: Estimated prevalence of hypertension across the 7MM, 2010 25
Table 3: Forecast epidemiology of hypertension across the 7MM, 2010–16 26
Table 4: Estimated prevalence of dyslipidemia across the 7MM, 2010 31
Table 5: Forecast epidemiology of dyslipidemia across the 7MM, 2010–16 32
Table 6: Estimated prevalence of stroke across the 7MM, 2010 36
Table 7: Forecast epidemiology of stroke across the 7MM, 2010–16 37
Table 8: Geographical segmentation of the global cardiovascular market, 2010 40
Table 9: Global market size of major cardiovascular drug classes ($m), 2010–16 44
Table 10: Sales of leading antihypertensive drugs ($m), 2010 49
Table 11: Sales of leading antidyslipidemic drugs ($m), 2010 56
Table 12: Sales of leading antithrombotic drugs ($m), 2010 68
Table 13: Snapshot of the major antithrombotic drugs under development 74
Table 14: Sales of leading “Other” cardiovascular drugs ($m), 2010 76
Table 15: Sales of leading cardiovascular brands ($m), 2010 78
Table 16: Leading pipeline drugs in the cardiovascular market, 2010 (part 1) 87
Table 17: Leading pipeline drugs in the cardiovascular market, 2010 (part 2) 88
Table 18: An overview of LCZ696 91
Table 19: An overview of cinaciguat 92
Table 20: An overview of riociguat 94
Table 21: An overview of Livalo 95
Table 22: An overview of dalcetrapib 97
Table 23: An overview of anacetrapib 98
Table 24: An overview of darapladib 99
Table 25: An overview of Xarelto 101
Table 26: An overview of apixaban 103
Table 27: An overview of Brilinta 105
Table 28: An overview of betrixaban 106
Table 29: Sales of leading players in the global cardiovascular market ($m), 2010 111
Table 30: Pfizer sales of leading cardiovascular brands ($m), 2010 113
Table 31: Pfizer late-stage cardiovascular pipeline, 2010 116
Table 32: Sanofi sales of leading cardiovascular brands ($m), 2010 120
Table 33: AstraZeneca sales of leading cardiovascular brands ($m), 2010 125
Table 34: AstraZeneca late-stage cardiovascular pipeline, 2010 127

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Table 35: Novartis sales of leading cardiovascular brands ($m), 2010 131
Table 36: Novartis late-stage cardiovascular pipeline, 2010 134
Table 37: BMS sales of leading cardiovascular brands ($m), 2010 137
Table 38: BMS cardiovascular portfolio, 2010 139
Table 39: Merck sales of leading cardiovascular brands ($m), 2010 142
Table 40: Merck late-stage cardiovascular pipeline, 2010 144

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Executive Summary
Overview and epidemiology of cardiovascular disorders
Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke,
atherosclerosis, thrombosis, and coronary artery disease.
The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable
factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet,
obesity, tobacco consumption, stress, and physical inactivity.
Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336
million cases in the seven major markets (7MM).
According to World Health Organization (WHO) estimates, stroke was one of the leading causes of
mortality in 2010, and its prevalence rate across the seven major markets was estimated at
approximately 0.2%.
Global market analysis
The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in
2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall
market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing
generic presence, the US witnessed a resurgence in 2009.
Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global
market share of 22%. Novartis’s Diovan led the antihypertensives segment with $3.6bn in sales,
followed by Benicar with sales of $2.9bn. Pfizer’s Norvasc, one of the blockbusters in this sub-category
suffered strong sales erosion and lost significant market share to Diovan.
Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within
antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of

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Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE)
inhibitors have also been on the decline due to competition from ARBs and increased genericization.
Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a
market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact
future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential
blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market
created by the genericization of Lipitor.
Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is
forecast to deliver strong growth in the next two years owing to the commercialization of recently
approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMS’s apixaban.
The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of
drug therapy. However, promising products such as Sanofi’s Multaq are expected to provide a fillip to
the segment by 2013.
Pipeline analysis
Anticoagulants are expected to be the subject of intensive R&D activity, with the presence of promising
products such as BMS/Pfizer’s apixaban and Bayer/J&J’s Xarelto. Since most of the factor Xa inhibitors
are in oral form, they are expected to widen the market significantly.
The superior effectiveness and better bleeding profile of Brilinta (ticagrelor) over Plavix make it a key
antithrombotic drug that could be a major player in acute coronary syndrome (ACS). Brilinta also has a
potential therapeutic advantage in atherosclerosis and can be administered to 15–30% of
atherosclerosis patients who do not respond to Plavix. Moreover, its use could be initially confined to
ACS with no significant patient monitoring anticipated for respiratory or cardiac function or post-
marketing surveillance requirements.
LCZ696, one of Novartis’s key pipeline products, delivered favorable Phase IIb results. The data
demonstrated that LCZ696 not only improved blood pressure significantly in patients with mild-to-

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moderate hypertension but also provided complementary action with neprilysin inhibition and ARB
blockade.
Merck/Portola’s betrixaban appears to have a differentiated half-life (19 hours), competitive
bioavailability, and minimal renal excretion which theoretically could result in a superior bleeding profile
and allow recruitment of patients irrespective of renal function. In its Phase IIb results announced in
March 2010, betrixaban demonstrated strong bleeding benefits over warfarin, further strengthening its
case.
The antidyslipidemic category is set to undergo significant declines in sales owing to the patent expiry
of Lipitor. Falling sales could be rescued with the approval of dalcetrapib, a potent CETP inhibitor that
treats dyslipidemia through increasing the levels of HDL cholesterol. Early trial results indicate that
anacetrapib is a more potent CETP inhibitor than dalcetrapib. However, the early entry of dalcetrapib
could serve to establish it as a prescription drug of choice, thus giving it a significant advantage over
anacetrapib.
Competitive landscape
The global cardiovascular market registered $170bn in sales in 2010. Pfizer retained its position as the
market leader with $15.2bn in 2010 sales, led by key brands such as Lipitor, Norvasc, Caduet, and
Viagra.
The top 10 companies in the cardiovascular market registered $76.4bn in combined sales in 2010,
accounting for a substantial 44.9% of the global cardiovascular market.
Sanofi remained the second largest company, registering $10.5bn in 2010 sales and a 6.2% share of
the global cardiovascular market. The company has benefited strongly from the performance of
Lovenox and Plavix, which generated $3.8bn and $2.8bn respectively in 2010 sales.
AstraZeneca was the third largest company in the global cardiovascular market, recording sales of
$9.4bn in 2010. Sales were strongly driven by the blockbuster drugs Crestor and Atacand

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Novartis was the fourth largest company, with 2010 sales of $8.6bn. Its position was strongly supported
by the ARBs, ARBs in combination with diuretics, and the statins. All Novartis’s leading brands,
including Diovan ($3.6bn), Co-Diovan ($2.4bn), and Exforge ($904m) registered strong Y-o-Y growth in
2010.
Merck and BMS were the other leading companies, registering 2010 sales of $7.5bn and $8.4bn
respectively.

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Chapter 1 Overview and epidemiology of
cardiovascular disorders
Summary
Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke,
atherosclerosis, thrombosis, and coronary artery disease.
The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable
factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet,
obesity, tobacco consumption, stress, and physical inactivity.
Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336
million cases in the seven major markets (7MM).
According to World Health Organization (WHO) estimates, stroke was one of the leading causes of
mortality in 2010, and its prevalence rate across the seven major markets was estimated at
approximately 0.2%.
Introduction
This chapter provides a background to the cardiovascular therapeutic category by identifying the key
indications, providing detailed overviews of each of the indications, and listing their current and forecast
prevalence through 2016. In accordance with the scope of this report, the primary focus of this chapter is
restricted to hypertension, dyslipidemia, and stroke. The chapter also provides a brief overview of the
predisposing factors that lead to cardiovascular diseases.
Among the various cardiovascular diseases, dyslipidemia had the highest prevalence in 2010, with 336
million reported cases. The following table provides the consolidated estimates of the prevalence of
cardiovascular diseases discussed in this chapter.

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Table 1: Estimated prevalence of cardiovascular disorders across the 7MM, 2010
Country Hypertension (000s) Dyslipidemia (000s) Stroke (000s)
France 16,372 31,877 80
Germany 29,612 54,780 127
Italy 22,376 20,582 112
Spain 18,715 9,712 90
UK 23,649 29,625 103
EU5 110,724 146,576 512
US 76,198 162,716 759
Japan 47,085 26,710 247
Total 234,007 336,002 1,518
Source: American Heart Association, National Health Statistics, CDC, WHO BUSINESS INSIGHTS
Risk factors
Predisposing risk factors
Predisposing factors are those conditions and lifestyle habits that put people at a greater risk of developing
cardiovascular diseases. They can be broadly classified into two categories: immutable factors such as age,
sex, heredity, and modifiable factors that are largely lifestyle-related such as diet, tobacco consumption,
physical inactivity, obesity, and stress.
While having a certain predisposing factor or set of factors increases the likelihood of an individual
developing a cardiovascular disease, it does not always lead to the condition. Conversely, the absence of a
predisposing factor does not nullify the possibility of the individual developing a particular disease. In
essence, the factors have a cumulative effect, that is, the presence of a large number of identifiable factors
increases the probability of an individual developing cardiovascular disease.
Owing to the statistical relationship between these factors and cardiovascular disease, a treatment for the
predisposing factor may not entirely eliminate the possibility of the disease. Similarly, if the factor is very
prominent in an individual, treating it even with a very effective treatment may not reduce the disease risk.

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However, studies have shown that the treatment of predisposing risk factors such as smoking, high blood
pressure, and high cholesterol, can reduce the likelihood of a heart attack.
Given the rather complicated nature of this association between predisposing/risk factors and cardiovascular
disease, demonstrating it is considered to be a major scientific challenge. For instance, a disease such as
atherosclerosis can be caused by various factors and is found to some degree in all individuals. Thus, it is
difficult to design and implement studies that show the effectiveness of a particular treatment.

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Figure 1: Cardiovascular disease etiology
Non-manageable
Age
Sex
Heredity
Race
Predisposing factors
Manageable
Diet
Smoking
Physical inactivity
Stress
Substance abuse
Risk factors
Glucose intolerance
Dyslipidemia
Diabetes
High blood pressure
Myocardial infarction
Acute coronary syndrome
Congestive heart failure
Coronary artery disease
Peripheral artery disease
Pulmonary hypertension
Stroke
Cardiovascular diseases
Arteriosclerosis
Thrombosis
Clinical manifestations
Angina pectoris
Aneurysm
Edema
Non-manageable
Age
Sex
Heredity
Race
Predisposing factors
Manageable
Diet
Smoking
Physical inactivity
Stress
Substance abuse
Risk factors
Glucose intolerance
Dyslipidemia
Diabetes
High blood pressure
Myocardial infarction
Acute coronary syndrome
Congestive heart failure
Coronary artery disease
Peripheral artery disease
Stroke
Arteriosclerosis
Thrombosis
Clinical manifestations
Angina pectoris
Aneurysm
Edema
Source: Yale Heart Book BUSINESS INSIGHTS

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Modifiable risk factors
Modifiable risk factors primarily include high blood pressure, high cholesterol, tobacco consumption, and type
2 diabetes. Research has indicated that the treatment of the major risk factors can greatly reduce the
possibility of a heart attack. Moreover, some of these factors are lifestyle-related, and a combination of diet
and exercise can work as a protective factor and reduce the likelihood of cardiovascular disease.
Figure 2: Cardiovascular risk factors and definitions
2 hour glucose levels of 140–199mg/dL (7.8 to
11.0mmol) on the 75g oral glucose tolerance test
Type 2 diabetes Fasting plasma glucose of 126mg/dL or 7mmol/L
Low HDL
Hypertriglyceridemia
High LDL
Hypertension
40mg/dL
200mg/dL
160mg/dL
140/90mmHg
Impaired glucose tolerance
Risk Factor Definition
2 hour glucose levels of 140–199mg/dL (7.8 to
11.0mmol) on the 75g oral glucose tolerance test
Type 2 diabetes Fasting plasma glucose of 126mg/dL or 7mmol/L
Low HDL
Hypertriglyceridemia
High LDL
Hypertension
40mg/dL
200mg/dL
160mg/dL
140/90mmHg
Impaired glucose tolerance
Risk Factor Definition
Source: Yale Heart Book BUSINESS INSIGHTS
Hypertension
High blood pressure or hypertension is the most important risk factor for cardiovascular disease.
Physiologically, it is defined as a condition wherein the pressure of the blood flowing through blood vessels
remains high for a prolonged period irrespective of the body’s need. An increased blood pressure leads the
heart to work harder, which makes the heart and arteries more susceptible to injury. Hypertension further
increases the risk of incidents such as heart attack, heart failure, and atherosclerosis.

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There are several factors that lead to hypertension, such as a sedentary lifestyle, alcohol consumption, high
sodium diet, high fat diet, high alcohol intake, obesity, and age. Furthermore, people with indications such as
diabetes mellitus or kidney disease, and even those with social or occupational stress, are in the high-risk
group.
Figure 3: Definition and classification of hypertension
Normal blood
pressure
Stage I
hypertension
Occasional
or
intermittent
Low
140–159mm
Hg
90–99mm Hg
Normal or
rare
None
Less than
130mmHg
Less than
85mm Hg
Category
Blood
pressure
elevations
Risk of CVD
Systolic
blood
pressure
Diastolic
blood
pressure
Stage II
hypertension
Sustained 160mm Hg 100mm Hg
Stage III
hypertension
Marked and
sustained
Advanced
161–179mm
Hg
101–109mm
Hg
Progressive
Normal blood
pressure
Stage I
hypertension
Occasional
or
intermittent
Low
140–159mm
Hg
90–99mm Hg
Normal or
rare
None
Less than
130mmHg
Less than
85mm Hg
Category
Blood
pressure
elevations
Risk of CVD
Systolic
blood
pressure
Diastolic
blood
pressure
Stage II
hypertension
Sustained 160mm Hg 100mm Hg
Stage III
hypertension
Marked and
sustained
Advanced
161–179mm
Hg
101–109mm
Hg
Progressive
Source: Writing Group of The American Society of Hypertension, 2005 BUSINESS INSIGHTS
Diagnosis, treatment and management
In over 90% of cases there may be no identifiable cause of hypertension, in which case the condition is
known as essential hypertension. Some researchers believe that this may be due to hormonal factors, which
control the salt-handling ability of the kidney, while others believe that it is genetically determined and
environmentally controlled. In the remaining 10% of cases, hypertension may be secondary in nature as a
consequence of another medical problem, such as kidney disorders, adrenal tumors, or some drugs.

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Diagnosis of hypertension involves inspection of the eyes, examination of the heart, arterial blood flow check,
examination of the kidneys, and checking for an enlarged thyroid. There are also some costly and less
frequently used diagnostic methods for hypertension, such as an echocardiogram (ECHO), 24-hour blood
pressure monitoring, and stress test.
Treatment of essential hypertension targets symptomatic relief, which implies achieving a target blood
pressure. Treatment of secondary hypertension involves symptomatic relief but also treatment of the primary
cause of elevated blood pressure. All treatment strategies include strict dietary regulations.

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Figure 4: Hypertension treatment options
Note: ACEI = ACE inhibitors; ARB = angiotensin II receptor blockers; BB = beta-blockers; CCB
= calcium channel blockers; TD = thiazide diuretics.
Source: Seventh Report of the Joint National Committee on the Prevention,
Detection, Evaluation and Treatment of High Blood Pressure
BUSINESS INSIGHTS
Epidemiology
As detailed in Table 2 the prevalence of hypertension was very high across all the 7MM (France, Germany,
Italy, Spain, UK, US, and Japan), with an estimated 234 million reported cases in 2010. The US accounted
for approximately 33% of the total cases, followed by Japan at 20%.

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In terms of prevalence rate, Spain led the way at 42.1%, followed by Japan at 36.9%. The average
prevalence rate across the 5EU was around 35.6%, significantly higher than that in the US at 24.3%.
Table 2: Estimated prevalence of hypertension across the 7MM, 2010
Country Prevalence (000s) Prevalence (%) Share (%)
France 16,372 26.2 7
Germany 29,612 35.7 13
Italy 22,376 37.9 10
Spain 18,715 42.1 8
UK 23,649 38.6 10
EU5 110,724 35.6 47
US 76,198 24.3 33
Japan 47,085 36.9 20
Total 234,007 31.1 100

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Forecast epidemiology
Table 3: Forecast epidemiology of hypertension across the 7MM, 2010–16
Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f)
France
Prevalence (000s) 16,372 16,495 16,619 16,744 16,869 17,051 17,149
Prevalence (%) 26.2 26.3 26.4 26.4 26.5 26.7 26.7
Germany
Prevalence (000s) 29,612 29,701 29,791 29,881 29,971 29,994 30,112
Prevalence (%) 35.7 35.8 36.0 36.1 36.2 36.2 36.4
Italy
Prevalence (000s) 22,376 22,388 22,401 22,413 22,426 22,474 22,471
Prevalence (%) 37.9 37.9 37.9 37.8 37.9 38.0 37.9
Spain
Prevalence (000s) 18,715 18,818 18,922 19,026 19,131 19,392 19,428
Prevalence (%) 42.1 42.3 42.7 42.5 42.7 42.8 43.0
UK
Prevalence (000s) 23,649 23,795 23,942 24,089 24,237 24,450 24,567
Prevalence (%) 38.6 38.7 38.8 38.9 38.6 38.8 38.9
5EU
Prevalence
(000s)
110,724 111,197 111,675 112,153 112,634 113,361 113,727
Prevalence (%) 35.6 35.7 35.7 35.8 35.9 36.0 36.0
US
Prevalence (000s) 76,198 77,335 78,488 79,659 80,847 82,584 83,475
Prevalence (%) 24.3 24.4 24.5 24.7 25.3 25.6 25.7
Japan
Prevalence (000s) 47,085 47,396 47,709 48,024 48,341 48,667 48,973
Prevalence (%) 36.9 37.2 37.5 37.8 38.4 38.8 39.1
Total
Prevalence
(000s)
234,007 235,928 237,872 239,836 241,822 244,612 246,175
Prevalence (%) 31.1 31.2 31.3 31.4 31.8 32.1 32.1
Source: American Heart Association, National Health Statistics, CDC, WHO,
Business Insights
BUSINESS INSIGHTS

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The prevalence of hypertension is forecast to grow from 234 million in 2010 to 246 million in 2016 across the
seven major markets. In 2016, the US is still expected to be the largest market for hypertension, with an
anticipated 83 million sufferers, followed by Japan at 49 million.
In terms of prevalence rate, Spain is expected to lead the way in 2016 at 43% followed by Japan at 39.1%.
The average prevalence rate across the 5EU in 2016 is expected to be around 36%, a slight increase over
2010. Furthermore, an increase in the mean age of the population is expected to put a significant number of
individuals at hypertensive risk.
According to the International Society of Hypertension, there is a clear recognition of hypertension as a major
public health issue across all the 7MM. Although the awareness level differs from country to country, lifestyle
changes in general are expected to play a significant role in reducing the risk factors among larger
population groups.
Dyslipidemia
Dyslipidemia refers to an alteration in the level of blood lipids. It is of two types, hyperlipidemia and
hypolipidemia, with the commonest being hyperlipidemia.

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Figure 5: Types of lipoproteins
Chylomicrons
Very low density
lipoprotein (VLDL)
Intermediate density
lipoprotein (IDL)
Low density
lipoproteins (LDL)
High density
lipoproteins (HDL)
Carries triglycerides from food in intestines
to liver, skeletal muscle, and adipose tissue.
Carries newly synthesized triglycerides from
liver to adipose tissue.
Intermediate between VLDL and LDL (very
low blood levels).
Carries cholesterol from liver to other body
parts (“bad cholesterol’)
Collects cholesterol from body parts and
carries to the liver (“good cholesterol”).
Type Description Hyperlipidemia
Chylomicrons
Very low density
lipoprotein (VLDL)
Intermediate density
lipoprotein (IDL)
Low density
lipoproteins (LDL)
High density
lipoproteins (HDL)
Carries triglycerides from food in intestines
to liver, skeletal muscle, and adipose tissue.
Carries newly synthesized triglycerides from
liver to adipose tissue.
Intermediate between VLDL and LDL (very
low blood levels).
Carries cholesterol from liver to other body
parts (“bad cholesterol’)
Collects cholesterol from body parts and
carries to the liver (“good cholesterol”).
Type Description Hyperlipidemia
Source: Business Insights BUSINESS INSIGHTS
Lipids include cholesterol, cholesterol esters, phospholipids, and triglycerides, which are transported in the
blood stream as large molecules called lipoproteins. There are five major lipoprotein families, as illustrated in
the above figure.
The international committee for the evaluation of hypertriglyceridemia as a vascular risk factor has classified
hypertriglyceridemias (hyperlipidemias) into three groups:
Isolated moderate hypertriglyceridemia – triglycerides 200–400mg/dL, total cholesterol <200mg/dL.
Mixed hypertriglyceridemia – triglycerides 200–400mg/dL, LDL cholesterol >130mg/dL.
Severe hypertriglyceridemia – triglycerides >400mg/dL.

29
Diagnosis, treatment, and management
Diagnosis of dyslipidemia involves the measurement of blood levels of various lipoproteins. The National
Cholesterol Education Program Adult Treatment Panel III Guidelines provide a comprehensive approach to
the treatment of dyslipidemia. It primarily focuses on controlling elevated LDL-cholesterol (LDL-C) levels.
Figure 6 illustrates the interpretation of blood lipid levels.
Figure 6: Interpretation of blood lipid levels
Total cholesterol
Lipid
LDL cholesterol
HDL cholesterol
< 200 Desirable
Blood levels (mg/dL) Comment
200–239 Borderline high
> 240 High
< 100 Optimal
100–129
Near optimal/ above
optimal
130–159 Boderline high
160–189 High
≥ 190 Very high
< 40 Low
≥ 60 High
Total cholesterol
Lipid
LDL cholesterol
HDL cholesterol
< 200 Desirable
Blood levels (mg/dL) Comment
200–239 Borderline high
> 240 High
< 100 Optimal
100–129
Near optimal/ above
optimal
130–159 Boderline high
160–189 High
≥ 190 Very high
< 40 Low
≥ 60 High
Source: National Cholesterol Education Program Adult Treatment Panel III
Guidelines
BUSINESS INSIGHTS
The priority of dyslipidemia treatment is reduction of LDL-C to less than 100mg/dL and the ratio of total
cholesterol to HDL-cholesterol (HDL-C) to less than four. The American Heart Association (AHA)
recommends a set of guidelines for the treatment of dyslipidemia, which is also designed for lowering LDL
levels. The following figure illustrates LDL levels and therapy patterns.

30
Figure 7: LDL levels and therapy patterns
Level for drug
consideration
Therapy Goal of therapyLDL cholesterol
≥ 220mg/dL
≥ 190mg/dL
160–189mg/dL
≥ 160mg/dL
≥ 130 mg/dL
100–129mg/dL
Diet and drug ≤ 160mg/dL
Diet (drug therapy
optional)
≤160mg/dL
Diet (drug therapy
optional)
≤ 100mg/dL
Without coronary
heart disease
and with ≥ 2 risk
factors
Without coronary
heart disease and
with < 2 risk
factors
With coronary
heart disease
Level for drug
consideration
Therapy Goal of therapyLDL cholesterol
≥ 220mg/dL
≥ 190mg/dL
160–189mg/dL
≥ 160mg/dL
≥ 130 mg/dL
100–129mg/dL
Diet (drug therapy
optional)
≤160mg/dL
Diet (drug therapy
optional)
≤ 100mg/dL
Without coronary
heart disease
and with ≥ 2 risk
factors
Without coronary
heart disease and
with < 2 risk
factors
With coronary
heart disease
Source: American Heart Association BUSINESS INSIGHTS
Epidemiology
Among all the cardiovascular diseases covered in this report, dyslipidemia had the highest prevalence, with
336 million affected patients across the 7MM in 2010. The US was the largest market, accounting for 48% of
the total prevalence followed by Germany at 16%.
The highest prevalence rate was recorded by Germany at 65.7%, followed by the US at 51.8%. The average
prevalence rate in the EU5 was comparable to the US at 47.1%. Out of the 7MM, Japan had the lowest
prevalence rate at 20.9%. Table 4 shows the estimated prevalence rate of dyslipidemia across the seven
major markets in 2010.

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Table 4: Estimated prevalence of dyslipidemia across the 7MM, 2010
France 31,877 51.0 9
Germany 54,780 65.7 16
Italy 20,582 34.9 6
Spain 9,712 21.9 3
UK 29,625 48.3 9
EU5 146,576 47.1 44
US 162,716 51.8 48
Japan 26,710 20.9 8
Total 336,002 44.6 100
The prevalence of dyslipidemia across the 7MM is forecast to increase from 336 million in 2010 to 356
million in 2016, at a CAGR of 0.97%. The US is expected to retain its position as the largest pool for
dyslipidemics, with an expected prevalence of 175 million in 2016.
In terms of prevalence rate, Germany is expected to retain its top spot in 2016, with an expected 68%,
followed by the US at 53.7% and France at 52.6%. The EU5 is forecast to have a prevalence rate of 48.4%,
lower overall than in the US. Of the 7MM, Japan is expected to have the lowest prevalence rate at 22.8% in
2016.

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Table 5: Forecast epidemiology of dyslipidemia across the 7MM, 2010–16
Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f)
France
Prevalence (000s) 31,877 32,183 32,491 32,802 33,117 33,399 33,716
Prevalence (%) 51.0 51.3 51.5 51.8 52.1 52.3 52.6
Germany
Prevalence (000s) 54,780 55,046 55,312 55,580 55,849 56,425 56,558
Prevalence (%) 65.7 65.8 66.0 66.1 67.4 68.1 68.0
Italy
Prevalence (000s) 20,582 20,676 20,770 20,865 20,960 21,114 21,182
Prevalence (%) 34.9 35.0 35.1 35.2 35.4 35.7 37.6
Spain
Prevalence (000s) 9,712 9,823 9,936 10,050 10,165 10,240 10,368
Prevalence (%) 21.9 22.1 22.3 22.6 22.5 22.6 22.9
UK
Prevalence (000s) 29,625 29,841 30,058 30,277 30,497 30,752 30,952
Prevalence (%) 48.3 48.5 48.7 48.9 48.6 48.8 49.0
5EU
Prevalence (000s) 146,576 147,569 148,567 149,574 150,588 151,930 152,776
Prevalence (%) 47.1 47.3 47.5 47.7 48.0 48.2 48.4
US
Prevalence (000s) 162,716 164,590 166,486 168,403 170,343 173,232 174,687
Prevalence (%) 51.8 51.9 52.1 52.2 53.2 53.7 53.7
Japan
Prevalence (000s) 26,710 27,034 27,362 27,694 28,030 28,222 28,605
Prevalence (%) 20.9 21.2 21.5 21.8 22.3 22.5 22.8
Total
Prevalence (000s) 336,002 339,193 342,415 345,671 348,961 353,384 356,068
Prevalence (%) 44.6 44.9 45.1 45.3 46.0 46.4 46.6
Business Insights
BUSINESS INSIGHTS

33
Cardiovascular diseases are a broad term, the definition of which includes a number of indications related to
the heart and the vascular network. These are interrelated indications, which tend to be linked in a complex
cascade; one may lead to another if not treated properly. Risk factors such as dyslipidemia and diabetes,
among others, may cause cardiovascular disease.
Arteriosclerosis/atherosclerosis
Arteriosclerosis is the thickening of the arteries and hence the loss of flexibility of the vessel walls. This leads
to a restricted supply of blood to the tissues and organs. Thickening of the vessel walls can occur for several
reasons, the most common being a build up of fats, known as plaques, on the artery walls. Arteriosclerosis
leads to complications such as coronary artery disease (CAD), stroke, peripheral artery disease (PAD),
aneurysms, and so on. Atherosclerotic plaques can also break, leading to thrombosis and probable
thromboembolism.
Thrombosis
Thrombosis is the formation of a blood clot, or thrombus, inside blood vessels, obstructing blood flow.
Thromboembolism is the condition wherein the blood clot breaks loose and is carried along the vessel, until it
clogs a narrower vessel. This may occur in the lungs (pulmonary embolism), brain (stroke), gastrointestinal
tract, or limbs (deep vein thrombosis-DVT).
Cardiac arrhythmias
Arrhythmias are heart rhythm problems, which occur when heart beats are not well coordinated owing to
improper electric impulses. This may cause the heart to beat too fast (tachycardia) or too slowly
(bradycardia). Arrhythmias are generally harmless and momentary, but frequent rhythm disturbances
increase the risk of stroke and congestive heart failure.
Myocardial infarction (MI)
Myocardial infarction, commonly known as heart attack, is a rapidly occurring myocardial necrosis due to
interruption of blood supply to a part of the heart. Angina is frequently classified according to
electrocardiogram (ECG) changes as non-ST segment elevation MI or subendocardial MI (NSTEMI –

34
necrosis with no ST elevation), and ST segment elevation MI or transmural MI (STEMI – necrosis with ST
elevation).
Acute coronary syndrome (ACS)
ACS is a term used to cover a group of clinical symptoms compatible with acute myocardial infarction, which
is chest pain due to insufficient blood supply to the heart muscle, resulting from coronary artery disease.
Congestive heart failure (CHF)
CHF is a condition wherein the heart fails to supply blood to the various parts of the body. This may be due
to narrowed arteries, myocardial infarction, heart valve disease, high blood pressure, cardiomyopathy, or
congenital abnormalities.
Coronary artery disease (CAD)
CAD results from the effects of atherosclerotic plaque formation in coronary arteries. The reduction in blood
supply to the heart muscles will reduce the heart’s efficiency and can cause heart failure. One of the first and
major symptoms of this condition is angina.
Peripheral artery disease (PAD)
PAD is a vascular disorder in which the thickening of arteries causes reduction in blood flow to limbs, leading
to intermittent leg pain while walking. The disease is an indicator of atherosclerosis. It leads to sores (that do
not heal) and gangrenes.
Pulmonary hypertension is a disorder of the pulmonary circulatory system, wherein the pulmonary arteries
and capillaries become narrowed or blocked by emboli. This causes build up of pressure in the arteries,
which is translated to the right ventricle, unlike hypertension where the left ventricle is affected. It can also
lead to heart failure.

35
Angina pectoris
Angina pectoris is severe chest pain due to ischemia (lack of blood and oxygen supply) of the myocardium.
The main causes of ischemia are blockade or spasm of coronary vessels. Angina can occur during activity
(stable angina), which is most common, or during rest (unstable angina).
Stroke
The WHO estimates that 15 million people suffer from stroke each year worldwide, 5.7 million of whom die.
This makes stroke the second-leading cause of death globally, responsible for 9.7% of deaths. These WHO
estimates also indicate that the share of deaths due to stroke may rise to 12.1% globally in 2030. A stroke
occurs when brain cells die owing to a lack of blood supply, resulting from thrombosis, embolism, or
hemorrhage. This may lead to permanent neurological damage. Some studies have concluded that transient
ischemic attack (TIA), caused by extracranial emboli or atherosclerosis of intracranial small arteries, may be
considered a warning signal for strokes.
Strokes may be classified as ischemic or hemorrhagic. Ischemic stroke involves decreased blood supply to
parts of the brain, leading to brain cell death and thus brain dysfunction. Hemorrhagic stroke is due to rupture
of blood vessels or abnormal vascular structure, causing accumulation of blood in a part of the brain. The
majority of strokes (80%) are ischemic in nature.
Epidemiology
Table 6 shows the prevalence of stroke across the seven major markets in 2010. Epidemiological data
indicates a prevalence of 0.2% in 2010 for stroke across the major markets. Countries such as the US,
Spain, Germany, Italy, UK, and Japan had a relatively high prevalence when compared with France.

36
Table 6: Estimated prevalence of stroke across the 7MM, 2010
France 80 0.1 5
Germany 127 0.2 8
Italy 112 0.2 7
Spain 90 0.2 6
UK 103 0.2 7
EU5 512 0.2 34
US 759 0.2 50
Japan 247 0.2 16
Total 1518 0.2 100
The overall patient potential for stroke is expected to rise from 1.5 million in 2010 to 1.6 million in 2016 with
the prevalence rate remaining constant at 0.2%.

37
Table 7: Forecast epidemiology of stroke across the 7MM, 2010–16
Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f)
France
Prevalence (000s) 80 80 80 80 80 80 80
Prevalence (%) 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Germany
Prevalence (000s) 127 127 127 127 127 127 127
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Italy
Prevalence (000s) 112 112 112 112 112 112 112
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Spain
Prevalence (000s) 90 91 91 91 91 92 92
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
UK
Prevalence (000s) 103 103 104 104 110 112 112
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
5EU
Prevalence
(000s)
512 513 514 514 520 523 523
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
US
Prevalence (000s) 759 764 769 774 779 783 788
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Japan
Prevalence (000s) 247 251 255 259 264 271 273
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Total
Prevalence
(000s)
1,518 1,528 1,538 1,547 1,563 1,577 1,584
Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2
Business Insights
BUSINESS INSIGHTS

38
Chapter 2 Global market analysis
Summary
The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in
2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall
market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing
generic presence, the US witnessed a resurgence in 2009.
Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global
market share of 22%. Novartis’s Diovan led the antihypertensives segment with $3.6bn in sales,
followed by Benicar with sales of $2.9bn. Pfizer’s Norvasc, one of the blockbusters in this sub-category
suffered strong sales erosion and lost significant market share to Diovan.
Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within
antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of
Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE)
inhibitors have also been on the decline due to competition from ARBs and increased genericization.
Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a
market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact
future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential
blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market
created by the genericization of Lipitor.
Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is
forecast to deliver strong growth in the next two years owing to the commercialization of recently
approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMS’s apixaban.
The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of
drug therapy. However, promising products such as Sanofi’s Multaq are expected to provide a fillip to
the segment by 2013.

39
Introduction
The global cardiovascular market, valued at $170bn in 2010, continues to remain a dynamic therapy area
with excellent growth potential owing to the vast pipeline of promising products. One of the most significant
developments in this market in the recent past has been the ruling of the Plavix case in favor of the
innovators Sanofi/Bristol Myers-Squibb (BMS) in April 2010. According to this judgment, Apotex, which
briefly infringed on Plavix’s ’265 patent by launching clopidogrel generics, is liable to pay economic damages
to the innovators. Moreover, Plavix is patent-protected in the US until November 2011. However, widespread
generic adoption is expected to negatively impact Plavix from 2012 onwards.
The antidyslipidemics category has also been exhibiting value erosion following the entry of generic Zocor
(simvastatin) in the US in 2006. However, the imminent patent expiry of Pfizer’s Lipitor (atorvastatin) in 2011,
is expected have significant ramifications for the cardiovascular market. Lipitor has already been losing
market share to generic simvastatin and the entry of atorvastatin generics are likely to further contribute to
the decline. Although the agreement with Ranbaxy regarding the manufacture and sale of a generic version
of Lipitor allows Pfizer to enjoy a six month post-patent expiration exclusivity, generic versions of Lipitor will
be marketed by Ranbaxy in November 2011. Thus, the revenue loss due to Lipitor patent expiration is likely
to impact the cardiovascular pharmaceutical market in 2012. In contrast, the growth outlook for the
antithrombotics segment is very promising with the expected launch of Pfizer/BMS’s apixaban and Bayer
J&J’s Xarelto.
This chapter focuses on many such strategic issues concerning the global cardiovascular market, with a
comprehensive review and analysis of the current market dynamics and recent key R&D events shaping the
market. The major cardiovascular therapeutic classes such as antihypertensives, antidyslipidemics,
antithrombotics, and cardiac therapies are analyzed alongside the leading brand dynamics for each of the
indications. The sales data captured in this report are global in scope and sourced from scientific journals,
company reports, and brokerage reports. Sales forecasts were made based on regression modeling, and
cause-and-effect analysis of data (based on growth drivers and resistors).

40
Market analysis by geography
The global cardiovascular market was valued at $170bn in 2010 and is expected to grow to a value of
$187bn in 2016 at a CAGR of 1.6%. The US accounts for about 40% of the entire cardiovascular market,
while the five major EU nations (UK, Germany, Italy, Spain, and France; collectively EU5) account for 18% of
the entire market, as shown in Table 8 and Figure 8. Both the US and EU5 regions are characterized by a
negative CAGR from 2010 to 2016, based on the expected decline in sales values of major blockbuster
drugs (such as Lipitor and Cozaar) after genericization. The growth is likely to be positive in Japan and the
rest of the world (ROW), (including Asia-Pacific (APAC), Latin America, Central America, Africa, and
Canada). Sales volumes in APAC will be driven by the strong adoption of generics, following the patent
expiry of the major blockbuster drugs in the cardiovascular segment. Cardiovascular drugs are also likely to
enjoy a sustained demand in Japan, owing to the aging population, and consequently an increase in age-
related diseases.
Table 8: Geographical segmentation of the global cardiovascular market, 2010
Geographical
region
Market size 2010 ($bn) Market share 2010
(%)
CAGR 2010–16 (%)
US 68 40 -8.5
EU5 30.6 18 -0.1
Japan 28.9 17 0.6
ROW 42.5 25 1.9
Total 170 100 1.6
Source: company reported sales BUSINESS INSIGHTS
The US market delivered $68bn in sales in 2010, and continued to be the single largest market with a share
of 40% of the global market. In 2007–08, the US market recorded a slight decline, but it staged a remarkable
recovery in 2009, driven by the statins and beta blockers. Nonetheless, the impending patent expiration of
major cardiovascular drugs, including Lipitor and Plavix, will lead to a decline in sales values in these
regions, and the US is likely to occupy only a 27% share of the global market in 2016.

41
Figure 8: Geographical segmentation of the global cardiovascular market, 2010 and
2016
27%
21%
20%
32%
40%
18%
17%
25%
US EU5 Japan ROW
2010 2016
100% = $170bn 100% = $187bn
27%
21%
20%
32%
40%
18%
17%
25%
USUS EU5EU5 JapanJapan ROWROW
2010 2016
100% = $170bn 100% = $187bn
Key events in the cardiovascular market
European approval for Rasilamlo
Rasilamlo, a single pill combination of a rennin inhibitor (aliskiren) and a calcium channel blocker
(amlodipine), manufactured by Novartis, received approval from the European Commission in April 2011 for
the treatment of high blood pressure in patients who are not controlled by either one of the antihypertensive
molecules. The approval is based on studies in more than 5,000 patients with mild to severe blood pressure,
and establishes the superiority of the combined therapy over the use of a single therapy. Novartis also filed a
request for EU approval for a triple combination product in May 2010. The triple combination product,
Amturnide, consists of aliskiren, amlodipine, and hydrochlorothiazide (a diuretic).
BMS/Pfizer’s apixaban likely to receive EU approval
Bristol-Myers Squibb (BMS) and Pfizer are likely to receive EU approval for their novel factor-Xa inhibitor,
apixaban (Eliquis), after receiving positive reviews from the Committee for Medicinal Products for Human

42
Use (CHMP). If granted, the approval will be for the use of apixaban for venous thrombolic events (VTE) in
adults who have undergone knee and hip replacement surgeries. The approval will closely follow study
results published by Lassen et al. (2010), which established the clinical superiority of apixaban in reducing
the incidence of venous thromboembolism (VTE) over Sanofi’s Lovenox (enoxaparin). The approval is likely
to pave the way for future usage of apixaban in other indications such as atrial fibrillation (AF).
Angiotensin receptor blockers (ARBs) may cause increased cancer risk
ARBs, which form the mainstay of hypertension treatment, have recently been found to have a link to an
increased risk of cancer in a meta-analysis published by Sipahi et al. (2010). The study involved analyzing
new cancer data from 61,590 patients from five clinical trials, common types of solid organ cancers involving
68,402 patients participating in five trials, and cancer deaths for 93,515 patients in eight trials.
The results of the study revealed that patients who were undergoing treatment with ARBs had a risk of new
cancer occurrence of 7.2%, compared with 6.0% risk of new cancer occurrence in control groups. Among
different types of solid organ cancers studied, only lung-cancer occurrence was found to be significantly
higher in patients treated with ARBs. Approximately 86% of all the patients in the trial received Boehringer
Ingelheim/Astellas’s Micardis (telmisartan). However, enough data was not generated to ascertain if this was
a class effect shared by all ARBs or an effect specific to any particular ARB.
While the repercussions of this finding on the ARB market in the short term are expected to be minimal,
further studies are expected to be undertaken, which could potentially raise concerns among the medical
community about the safety of ARBs. With stronger results to support this theory, ARB use would be likely to
become more selective, with applications reserved to specific patient groups such as the ACE inhibitor
intolerant population.
Following this publication, Boehringer Ingelheim claimed that these findings contradicted internal safety data
that indicated that Micardis has an acceptable safety profile in over 50,000 patients. AstraZeneca is yet to
review the study and issue a statement. Other leading drugs in the ARB class include Novartis’s Diovan,
Sanofi and BMS’s Avapro, and Daiichi Sankyo’s Benicar.

43
Crestor’s patent upheld in the US
AstraZeneca’s blockbuster antidyslipidemic Crestor, the biggest growth driver within the cholesterol-lowering
drugs category received a fillip after its patent was upheld by a US district court in June 2010. The
challengers – Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and Par – claimed that the drug’s original
patent filing by AstraZeneca’s partner, Shionogi, omitted material information. However, after a four-month
trial that began in February 2010, the court concluded that Crestor’s ’314 patent is valid until 2016, and none
of the generic challengers would be allowed to file abbreviated new drug approvals (ANDAs) before the
patent expiration date.
Crestor is currently the only branded statin in the US market that is witnessing positive growth and the court
judgment is expected to improve its prospects through the forecast period. The ruling also had a positive
impact on the company’s stock, with a 9% increase in its share price on the London Stock Exchange (LSE)
following the news.
Plavix boxed warning for poor metabolizers
Sanofi/BMS’s Plavix received a boxed warning to its US label in March 2010, indicating the diminished
effectiveness of the drug in patients with a variant of the CYP2C1P liver enzyme, which can lead to reduced
formation of the active metabolite. According to the label, this pool of patients, termed as poor metabolizers,
represents “approximately 14% of Chinese, 4% of blacks, and 2% of Caucasians.” The warning also includes
information about genetic tests to identify such patients.
Further, the FDA added that this group is less likely to benefit from Plavix and is at a high risk for heart
attack, stroke, and cardiovascular death. Although the information about poor metabolizers was added to the
label in May 2009 as a precaution, further evidence has prompted the companies to extend it to a warning.
This was based on a study in 40 subjects, with 10 each in the four metabolizer types, which found that the
poor metabolizers had notably lower levels of Plavix and antiplatelets (FDA Drug Safety Communication,
2010; www.fda.gov).

44
Market analysis by drug class
The global cardiovascular market registered sales of $170bn in 2010. Antihypertensives accounted for about
22% of the market, with total sales of about $37.7bn. Antithrombotics accounted for about 11% of sales in
2010, with total revenues of $18.7bn. However, the antithrombotics category is likely to experience a slower
decline than the other drug classes, owing to the relatively rapid innovation in the warfarin-replacement
market.
Sales in the major drug classes are shown in Table 9.The forecast sales of the various drug classes are
based upon the forecast sales of existing drugs only; these numbers to not take into account pipeline drugs
that are likely to be approved over the forecast period.
Table 9: Global market size of major cardiovascular drug classes ($m), 2010–16
Drug
class
2010 2011 2012 2013 2014 2015 2016 CAGR
2010–
16 (%)
Antihyper
-tensives
37,657 36,392 34,307 30,791 29,637 29,283 28,413 -4.6
Antidys-
lipidemics
29,899 29,822 25,230 24,744 24,459 23,828 20,156 -6.4
Antithrom
-botics
18,687 18,185 14,403 13,030 14,294 15,360 16,126 -2.4
Others 84,216 89,306 95,240 101,544 108,238 115,199 122,206 6.4
Total 170,460 173,706 169,179 170,109 176,629 183,671 186,901 1.6
A comparison of the current market share of the major drug classes and future, projected market share (as
shown in Figure 9) indicates a future decline in the market share of all three major drug classes. This is
concomitant with the likely decrease in sales values after patent-expiration of major drugs, especially in the
antihypertensive (Cozaar) and antidyslipidemic (Lipitor) categories.

45
Figure 9: Global market share of major cardiovascular drug classes (%), 2010–16
22%
18%
11%
49%
15%
11%
9%
65%
Antihypertensives Antidyslipidemics Antithrombotics Total others
2010 2016
100% = $170bn 100% = $187bn
22%
18%
11%
49%
15%
11%
9%
65%
AntihypertensivesAntihypertensives AntidyslipidemicsAntidyslipidemics AntithromboticsAntithrombotics Total othersTotal others
2010 2016
100% = $170bn 100% = $187bn
Source: Business Insights BUSINESS INSIGHTS
Novartis’s Diovan and Daiichi Sankyo’s Benicar were the leading antihypertensive drugs in 2010, with sales
of $3.6bn and $2.9bn respectively. Pfizer’s Norvasc, which was the leading antihypertensive until 2007, has
been registering a steady decline and Diovan has taken its place as the frontrunner within this segment.
Hypertension patients have increased pressure in their arteries leading to heightened risk of indications such
as hemorrhagic stroke, congestive heart failure, myocardial infarction, and kidney damage. Diuretics, ACE
inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers
(CCBs) are the key drugs prescribed for hypertension. Whereas Norvasc is a CCB, newer blockbusters such
as Diovan, Cozaar, Blopress, and Micardis are all ARBs. ARBs have emerged as the definitive successor to
CCBs and the largest prescribed category within antihypertensives. However, the entry of Cozaar generics in
2011 is expected to restrict the growth of ARBs. ACE inhibitors are another sub-category that is witnessing a
decline in sales due to rapid genericization and competition from ARBs. Growth in the hypertension market is
likely to be driven by novel therapies such as Novartis’s Tekturna and increased use of ARBs and their
combinations. Another trend observed in this market is the increased use of combination therapies, which
helps to build patience compliance by reducing the pill burden and intensity of side effects. Some frequently

46
used combinations include an ACE-I or ARB with CCB and a diuretic. Rasilamlo is one such combination
product, manufactured by Novartis. It is a combination of an ARB (aliskiren) and a CCB (amlodipine).
Antidyslipidemics were the second largest drug class within the cardiovascular market, registering global
sales of $29.9bn in 2010, with a total market share of 18%.
Antihypertensives
Introduction
Antihypertensives represent the largest drug class within the cardiovascular market, accounting for 22% of
the overall market. The major drug classes falling within this category are:
angiotensin receptor blockers (ARB)
calcium channel blockers (CCB)
ACE inhibitors (ACE-I)
diuretics
beta blockers.
ARBs are a recently introduced class of antihypertensives that are increasingly prescribed and considered to
be one of the growth drivers in this market. Angiotensin II is a blood vessel constrictor that causes
vasoconstriction throughout the body, and angiotensin II receptor antagonists are known to have good
efficacy and side-effect profiles.
The antihypertensives market is expected to undergo value erosion due to increased genericization of
leading therapies during the forecast period. However, increased adoption of recently launched novel
products such as Tekturna and Exforge is likely to provide an impetus to the market.
Antihypertensive drug classes
The antihypertensives market is complex, with the presence of an array of drug classes, ranging from
traditional therapies to novel combination products, each differing in its mechanism of action.

47
Blood pressure is maintained at a certain level by a chain of hormonal reactions in the body. The first of
these steps is the production of renin by the kidneys when they sense a lowered blood pressure. Renin, in
turn, helps in the production of angiotensin I, a protein that is converted to angiotensin II in the lungs by the
action of an enzyme (angiotensin-converting enzyme). Angiotensin II is a blood-vessel constrictor that
causes vasoconstriction throughout the body. It also leads to the secretion of aldosterone, an adrenal glands
hormone that helps in elevating blood pressure. This hormonal system is known as the renin-angiotensin-
aldosterone (RAA) hormonal system.
The difference between the antihypertensives’ drug classes lies in the step of the RAA hormonal system that
they act on. Two drug classes are known to have the maximum effect on this system, ARBs and ACE-Is.
ARBs block chemical receptors for angiotensin II so that it does not cause the arteries to constrict. ACE-Is,
on the other hand, prevent angiotensin I conversion to angiotensin II. ACE-Is may also have additional
effects, such as increasing the amount of chemicals that widen the arteries.
A third drug class, CCBs, acts on the calcium channel of the arteries. They prevent calcium from entering
into the artery muscles, keeping the arteries from contracting. One of the erstwhile leaders in the
antihypertensive market, Norvasc, is a CCB.
Beta-receptor blockers have been available for more than 35 years. They have been used for migraine,
congestive heart failure, cardiac arrhythmias, and even as a secondary prevention after myocardial
infarction. Beta blockers block sympathetic effects of the nervous system on the heart, reducing its workload,
which lowers blood pressure. Diuretics help the body in getting rid of excess fluid and salt through urine,
which helps to lower blood pressure.
Leading treatment brands by drug class
The top ten products in the cardiovascular market predominantly belong to the ARB sub-category, a trend
that is expected to continue up to 2012–13. However, rapid genericization across other sub-categories is
expected to negatively affect the prospects of ARBs. The popularity of ARBs has been primarily due to their
favorable side-effect profile, which has given them a competitive edge over several ACE inhibitors. In
addition, the ARB class has benefited from positive outcomes data from key studies such as VAL-HeFT and

48
LIFE, which have clearly demonstrated the superiority of ARBs over other sub-categories. The calcium
channel blockers, another leading sub-category is currently in decline due to the patent expiration of
Norvasc, the former top-selling drug.
Growth in the antihypertensive category is likely to be driven by products with novel mechanisms of action,
and combination therapies involving the use of multiple drugs with different mechanisms that complement
each other. Novartis’s Tekturna, launched in March 2007 was initially approved as an add-on therapy for
hydrochlorothiazide, ARBs, and ACE inhibitors and as a monotherapy for uncontrolled hypertensives.
However, a fixed dose combination of Tekturna/hydrochlorothiazide (HCT) was approved in 2009 for patients
likely to receive multiple therapies, thus boosting the growth prospects. In addition, Novartis is expected to
file two other Tekturna combinations in 2010 (Tekturna/amlodipine, and Tekturna/amlodipine/HCT), which if
approved could further help Tekturna consolidate its position as a potential blockbuster. Table 10 shows the
leading antihypertensive drugs in 2010.

49
Table 10:Sales of leading antihypertensive drugs ($m), 2010
Brand
name
Generic
name
Category Sales 2010
($m)
Market
share 2010
(%)
CAGR
2010–16
(%)
Patent
expiry
Diovan valsartan ARB 3,632 9.6 -14.6 2012
Benicar olmesartan ARB 2,891 7.7 0.8 2016
Blopress candesartan ARB 2,449 6.5 -3.8 2014*
Co-
Diovan
valsartan
/HCT
ARB 2,421 6.4 -8.8 2012
Cozaar losartan ARB 2,105 5.6 -14.0 Expired
2010
Aprovel irbesartan ARB 1,758 4.7 -3.3 NA
Norvasc amlodipine CCB 1,506 4.0 -7.5 Expired
Micardis telmisartan ARB 1,329 3.5 -10.8 2017*
Seloken metoprolol Beta
blocker
1,210 3.2 0.5 NA
Exforge amlodipine/
valsartan
CCB 904 2.4 3.4 2017
Total
leading
20,205 53.6
Others 17,452 46.4
Grand
total
37,657 100
* Japanese patent expiry
Source: company reported sales, FDA Orange Book BUSINESS INSIGHTS
Novartis’s Diovan led the antihypertensives market in 2010, registering sales of $3.7bn. Its HCT combination,
Co-Diovan achieved $2.4bn in sales and was the fourth largest selling antihypertensive drug in 2010. Pfizer’s
former blockbuster Norvasc, which was the market leader in 2007, has suffered severe sales erosion due to
genericization and is expected to exhibit a negative CAGR of -7.5% from 2010 to 2016.
Diovan’s market position has been strengthened further by its label expansion, supported by clinical
programs such as Val-HeFT (Valsartan Heart Failure Trial). This trial supported the use of Diovan for the

50
treatment of heart failure in cases where patients are not able to tolerate ACE-I. Another study, VALIANT
(VALsartan In Acute Myocardial Infarction Trial), supported its label expansion for patients who have suffered
a heart attack, to reduce cardiovascular death. A third study, VALUE (Valsartan Antihypertensive Long-term
Use Evaluation), supports its long-term use in preference to Norvasc. In 2007, Novartis launched Exforge
(Diovan/amlodipine), an expanded formulation of Diovan. The drug is a fixed dose combination, which is also
approved in the US for first-line use in the treatment of high blood pressure. As the revenues indicate,
Exforge has performed well in the US market, where fixed dose combinations have had moderate success at
best.
The second largest ARB, Benicar, generated $2.9bn in 2010. Blopress was the third largest selling
antihypertensive drug in 2010 and achieved $2.5bn in sales. Sales of Blopress can be attributed to the fact
that it is the first ARB to be approved for the treatment of chronic heart failure in three major markets (Japan,
US, and Europe). Cozaar was the fifth largest selling drug and generated revenues of $2.1bn. Over the past
few years, Cozaar’s sales have been largely driven by positive data from clinical trials such as LIFE
(Losartan Intervention For Endpoint Reduction in Hypertension) and RENAAL (Reduction of Endpoints in
Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II antagonist Losartan). However, following its
patent expiry in 2011, Cozaar’s sales are expected to erode significantly. One of the biggest drawbacks for
Cozaar has been the lack of a first-line congestive heart failure (CHF) claim worldwide, thus losing out to key
competitor brands such as Diovan.
Beta blockers are dominated by generics of atenolol, metoprolol, nadolol, pindolol, and propranolol. In 2008,
Forest laboratories launched a third-generation beta blocker, Bystolic (nebivolol) with a differentiated
mechanism of action. Bystolic was also being tested in patients with chronic heart failure, an indication for
which the FDA declined approval in February 2010. Despite this setback, there is still a potential market for
Bystolic in the elderly heart failure patient population, owing to positive data from a European pivotal CHF
trial (SENIORS). However, the biggest challenge for Bystolic is expected to be from generic Seloken
(metoprolol) and Coreg (carvedilol), which are known to have better safety profiles.

51
Key brands analysis
Diovan/Co-Diovan
Novartis’s Diovan franchise collectively generated sales of $6bn in 2010. Diovan and Co-Diovan have both
grown largely by capturing Norvasc sales following its patent expiry in 2007. Additionally, positive outcomes
data from key clinical studies such as Val-HeFT, VALIANT, and VALUE covering over 55,000 patients has
helped in extending the Diovan label beyond hypertension, thus consolidating its position in the market.
Clinical
The Val-HeFT trial supported Diovan’s claim in heart failure treatment for patients who cannot tolerate ACE-I
(Cohn et al., 1999) while VALIANT supported the drug’s label expansion for the reduction of cardiovascular
death in patients at high risk (with left ventricular failure or dysfunction) following a heart attack (Pfeffer et al.,
2000), and VALUE (Julius et al., 2004) supported long-term use when compared with Norvasc. The ABCD-
2V study (Bedigian et al., 2000) demonstrated that intensive diastolic blood pressure control also returned
diabetic patients’ return to normoalbuminuria.
Regulatory/commercial
Novartis launched two versions of Diovan HCT in the EU in 2009 with higher doses of diuretic (12.5mg and
25mg). The Diovan/amlodipine fixed-dose combination Exforge is one of the key products in the
antihypertensive market, registering $904m in sales in 2010. Exforge/HCT consists of a CCB (amlodipine),
an ARB (valsartan), and a diuretic (HCT), making it the first three-in-one combination treatment in the
antihypertensives market. These Diovan line extensions are part of Novartis’s strategy to offset lost sales
due to generic erosion following the loss of patent exclusivity in major EU markets in mid 2011.
Cozaar
Cozaar belongs to the ARBs, the most prescribed antihypertensive class. Angiotensin-II is a powerful blood-
vessel constrictor, and can cause vasoconstriction throughout the body. In general, angiotensin-II receptor
antagonists have very good efficacy and side-effect profiles. Their major advantage is a favorable side-effect
profile, such as the absence of cough.

52
Clinical
Cozaar is supported by indications for reduction in end-stage renal disease in diabetic patients, stemming
from the results of the RENAAL trial, and a stroke indication based on the LIFE study. RENAAL (Reduction
of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) was a
1,513 patient study of type 2 diabetics that assessed Cozaar’s impact on renal insufficiency and diabetic
nephropathy. Patients received Cozaar 50mg, 100mg, or placebo once daily, and were studied for 3.4 years.
Cozaar reduced the primary endpoint of either a doubling of serum creatinine, kidney failure, or death by
16% compared with placebo (p = 0.024). It also reduced the risk of progression to end-stage renal disease
requiring dialysis or kidney transplantation by 28% compared with placebo (p = 0.002) (Brenner et al., 2001).
LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) was revealed at the American College
of Cardiology meeting in March 2002. The trial compared Cozaar (Losartan) with atenolol (beta blocker) and
was designed to conclude after 1,040 cardiovascular events and a duration of four years. The overall results
were positive for Cozaar, as it showed a 13% risk reduction in the primary endpoint of cardiovascular
mortality, stroke, and myocardial infarction (p = 0.009) (Dalhöf et al., 1997). Cozaar reduced total mortality in
diabetics by 39% versus atenolol (p < 0.05). However, the data raised some questions. Stroke was the only
component of the primary endpoint that contributed a statistically significant improvement when assessed
separately, with risk of stroke reduced by 25% for patients taking Cozaar compared with atenolol (p = 0.001)
(Dalhöf et al., 1997). Data assessing Cozaar versus atenolol for the reduction of cardiovascular death and MI
were not statistically significant. Overall, the results of LIFE are viewed as impressive, given the sizable
mortality benefit that was observed with Cozaar, particularly in diabetics. Furthermore, LIFE was the first
outcomes study which showed that mechanisms are important; Cozaar led to similar blood pressure
reduction versus atenolol, yet delivered more powerful reductions in events. Cozaar will likely become the
ARB of choice in patients with hypertension and left ventricular hypertrophy, the latter being sometimes
viewed as a proxy for high-risk hypertension. Beta blockers are considered to be less effective than ACE-I
due to a lack of impact on the kidney. Cozaar received an expanded indication approval for the prevention of
stroke based on the LIFE data.

53
Cozaar lacks a first-line CHF claim worldwide, giving Diovan a significant competitive advantage.
Furthermore, the loss of patent protection in 2011 will further erode its sales and alter the dynamics of the
ARB market.
Benicar
Scientific
Benicar (olmesartan) is an ARB in the same class as Diovan and Co-Diovan, launched by a joint venture
between Forest and Sankyo in 2002. The results of a clinical study sponsored by Sankyo, and announced at
the American Society of Hypertension meetings in 2000, demonstrated Benicar’s statistically significant
superiority in starting doses over other ARBs, including Cozaar, Diovan, and Avapro, in the reduction of
diastolic pressure.
Clinical
Benicar is currently undergoing a trial called ROADMAP (Randomised Olmesartan and Diabetes
MicroAlbuminuria Prevention Study), a first-of-its-kind trial in which the effect of an ARB on the prevention of
microalbuminuria in patients with type 2 diabetes is being studied. The final results of this study are expected
in 2012.
Although Benicar was launched in 2002, it underwent an upsurge in sales after the commercialization of its
diuretic combination version with HCT (hydrochlorothiazide) in September 2003. Despite the lack of
significant differentiation from other ARBs, aggressive marketing has allowed Benicar to capture $2.9bn in
sales in 2010, making it the second largest selling drug in the cardiovascular category. Mylan challenged the
Benicar HCT combination in February 2007, but in March 2009 a lower court found the patent valid. The
Benicar patent is currently valid up to 2016, with peak sales expected in 2013. Sales are expected to
diminish after 2014 owing to increasing competition from the genericization of key brands, including
Blopress.

54
Antidyslipidemics
Introduction
Antidyslipidemics remain the second-largest drug class in the cardiovascular market, generating $29.9bn in
sales in 2010, and accounting for a market share of 18%. The antidyslipidemics drug class includes the
following sub-categories:
statins
fibrates
non-statins.
The current outlook of the dyslipidemia market has been shaped by several key events:
the appearance of Zocor generics in 2006
torcetrapib’s clinical setback in 2006
the FDA’s “not approvable” letter given to Merck’s Tredaptive in April 2008
Vytorin’s clinical data from the ENHANCE and SEAS trials.
In addition to all these developments, generic simvastatin has captured a significant share of the statins
market, leading to a decline in the sales of its branded counterparts Genericization of leading dyslipidemic
drugs such as Lipitor is likely to offset the growth driven by factors such as Crestor’s expanded approval
following the JUPITER (Justification for the Use of Statins in Primary Prevention ) trial data, which has the
potential to expand the market to include patients with normal levels of LDL and high C-reactive protein
(CRP). The market share of branded statins is declining due to recent patent expirations of key products
such as that of Zocor (2006).
Antidyslipidemic drug classes
The antidyslipidemics market consists of statins, fibrates, and a few other non-statin products, such as Zetia
(ezetimibe; Merck), and Niaspan (niacin; Abbott). Statins dominate the market, with most of the key drugs
falling into this class. Statins reduce blood cholesterol by lowering its production from the liver. Scientifically

55
referred to as HMG-CoA reductase inhibitors, statins block hydroxymethylglutaryl-coenzyme A reductase
(HMG-CoA reductase), the enzyme responsible for making cholesterol. They are prescribed for the treatment
of atherosclerosis (which causes stroke, heart attack, and chest pain) or for people with high blood
cholesterol levels.
Individual statins differ in their ability to lower blood cholesterol. Lipitor (atorvastatin) and Crestor
(rosuvastatin), for instance, are the most potent statins, while Lescol (fluvastatin) is the least potent. Statins
also differ in their interactions with other drugs, several of which are known to block the enzymes that
eliminate statins. When taken with statins, these may lead to increased statin levels, leading to inflammation
of the muscles, a condition called myopathy. Pravachol (pravastatin) and Crestor (rosuvastatin) are two
statins that are less likely to increase in level when taken with other drugs.
Fibrates are fibric acid derivatives that help in lowering blood triglyceride levels. Two ways in which fibrates
act are by reducing very low density lipoprotein (VLDL) (a triglyceride-carrying particle in blood) production in
the liver and speedy removal of triglycerides from the blood. They may also help in increasing HDL
cholesterol, although they are not effective in reducing LDL cholesterol levels.
Leading treatment brands by drug class
The antidyslipidemics market is dominated by statins, which are predominant among the top 10 brands. The
top ten brands in the market recorded sales of $27.8bn accounting for over 90% of the market. Lipitor was
the top-selling drug, occupying 39.7% of the market. However, Lipitor’s growth has stagnated in the past four
years. Other than Lipitor, some of the top brands include Crestor at $6.8bn and Zetia at $2.3bn. Table 11
illustrates the leading antidyslipidemic brands in 2010.

56
Table 11:Sales of leading antidyslipidemic drugs ($m), 2010
Brand
name
Generic
name
Category Sales 2010
($m)
Market
share 2010
(%)
CAGR
2010–16
(%)
Patent
expiry
Lipitor atorvastatin statin 11,873 39.7 -23.9 2011
Crestor rosuvastatin statin 6,767 22.6 3.8 2016
Zetia ezetimibe others 2,298 7.7 -1.8 2016
Vytorin ezetimibe/
simvastatin
statin 2,014 6.7 -8.2 2017
TriCor/TRI
LIPIX
fenofibrate fibrate 1,582 5.3 -7.4 Expired
Niaspan niacin GPR109
agonist
927 3.1 -53.0 2013
Lovaza omega-3-
acid ethyl
esters
- 819 2.7 -8.0
Mevalotin parvastatin statin 538 1.8 -6.9 Expired
Caduet amlodipine/
atorvastatin
statin 527 1.8 -6.1 2018
Zocor simvastatin statin 468 1.6 -13.6 Expired
Total –
leading
27,813 93
Others 2,086 7
Grand
total
29,899 100
Source: company reported sales, FDA Orange Book BUSINESS INSIGHTS
Sales of Lipitor have exhibited a steady decline in the past three to four years owing to the availability of
generic simvastatin since 2006 and also the emergence of Crestor as a leading treatment alternative. Sales
of Lipitor are set to decline at a CAGR of -23.9% from 2010 to 2016. AstraZeneca’s Crestor (rosuvastatin) is
another leading statin, with 2010 sales of $6.7bn. The sales of Crestor have continually risen since launch
and are likely to grow at a strong positive CAGR of 3.8%. Favorable clinical trial results, diminishing safety
concerns, and heavy promotions have assisted in boosting Crestor’s uptake. Furthermore, the increasing
use of high-potency statins among primary care physicians continues to drive growth for Crestor.

57
Pfizer’s Caduet (amlodipine and atorvastatin) registered sales of $527m in 2010 and is set to experience a
decline in sales at the rate of -6.1% from 2010 to 2016. The drug is a fixed dose combination of Lipitor and
Norvasc, and is one of the many options for treating high blood pressure and high cholesterol. Overall,
Caduet’s launch has been disappointing owing to slow managed-care acceptance, as the drug is viewed by
many formulary managers as a franchise extension strategy for Norvasc, which suffers from generic
competition.
Key brands analysis
Lipitor
Scientific
Lipitor (atorvastatin) is the largest selling drug globally, a mega blockbuster with 2010 sales of $11.8bn. It is
a liver-selective HMG-CoA reductase inhibitor and also one of the most researched drugs, backed by over
15 years of research data. The drug is estimated to lower LDL levels by 39–60%, depending on dosage. It
has received additional FDA approval for stroke, heart attack, chest pain (in patients with risk factors for
heart diseases), and some types of heart surgeries.
Clinical
Observational studies undertaken by Pfizer after the launch of generic Zocor have indicated that patients on
Lipitor had a 12% lower risk of a cardiovascular event compared with simvastatin. Lipitor patients also had a
15% lower risk of heart attack. Pfizer aggressively promoted the uptake of Lipitor 80mg formulations based
on the data from the REVERSAL (Reversal of atherosclerosis with aggressive lipid lowering), PROVEIT
(pravastatin or atorvastatin evaluation and infection therapy) and TNT (Treating to New Targets) studies. The
TNT results indicated a 22% reduction in cardiovascular events with 80mg, relative to 10mg, as well as only
a slight difference in muscle-related side effects including rhabdomyolysis (Waters et al., 2004). However, in
the IDEAL study Lipitor 80mg versus Zocor 20mg and 40mg indicated only an 11% relative reduction (non-
significant) in cardiovascular events, the primary composite endpoint (Pedersen et al., 2005). The trial
provided support for managed care to push generic Zocor over branded statins.
An analysis conducted after IDEAL indicated that patients taking Lipitor 80mg had their risk of experiencing
another heart attack reduced by 46%. Additionally, the risk of experiencing major coronary events, such as

58
heart attack, cardiac arrest, and cardiac death, was found to be reduced by 34% relative to simvastatin 20–
40mg doses. Lipitor 80mg also significantly reduced the risk of stroke, unstable angina, death, and
revascularization by 18% relative to 20–40 mg simvastatin. The safety profiles of the two groups were found
to be comparable.
The REVERSAL (Cannon et al., 2004) and PROVE-IT (Nissen et al., 2004) studies that compared Lipitor
80mg to Pravachol 40mg found Lipitor to be superior to Pravachol in reducing cardiovascular events
(PROVE-IT) and plaque volume (REVERSAL). Both the trials’ data showed Lipitor 80mg to be very safe over
the two-year period.
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events) compared the effects of an
aggressive lipid-lowering regimen with atorvastatin in patients after myocardial infarction versus a control
group receiving the usual care (lipid lowering drugs including statins at a dosage of 20–40mg, diet
modifications, and lifestyle changes). The results showed a reduction in non-fatal MI with atorvastatin by
47%, relative to the alternative therapeutic options (Koren et al., 2004).
The availability of generic simvastatin in the market, as well as competition from AstraZeneca’s Crestor, has
led to increasing therapeutic substitution and a declining market share for Lipitor. All this has resulted in a
waning of Lipitor’s dominance in the lipid control market, though it still continues to be the top-selling statin
globally. The drug is expected to lose patent exclusivity in the US in November 2011, which will lead to
severe erosion of sales.
Pfizer has recently filed a 5mg formulation of the drug in the EU for pediatric use. This filing is for the use of
Lipitor in six to 18 year-old patients who have familial hypercholesterolemia. The filing was supported by data
from new studies of the drug in heterozygous familial hypercholesterolemia (HeFH) patients in the age group
of six to 18 years, together with older data that was used to support its US pediatric filing. This is an effort by
the company to extend Lipitor’s patent protection; if approved, the drug would be eligible for patent term
extensions in some EU nations such as France and the UK. In the US, the drug has been approved for use
in adolescent HeFH patients since 2002.

59
Pfizer had been contesting Ranbaxy in a bid to delay generic competition for Lipitor until 2016. The two
companies finally entered into a settlement in June 2008. According to the settlement, Ranbaxy will not sell
the drug’s generic version until November 30, 2011. After this date, Ranbaxy will share a six-month market
exclusivity period with Cobalt (a subsidiary of Watson). Cobalt had filed an ANDA for the approval of a
product containing atorvastatin sodium, a salt form that is different from the atorvastatin calcium used in
Lipitor. In 2007, Pfizer filed a suit against Cobalt, leveling allegations of infringement of the enantiomer
patent. Pfizer and Cobalt had then (April 2008) entered into an agreement which gave Cobalt the right to
make authorized generics for a period of five years, wherein Pfizer will provide API through its subsidiary
Greenstone. In April 2009, Teva had also entered into a settlement with Pfizer.
Ranbaxy’s ability to manufacture generic Lipitor has become unclear owing to safety concerns raised by the
FDA. Inspections of Ranbaxy plants in India have found several quality control issues such as the lack of
proper GMPs and falsification of stability data. This has led to the halting of pending and future drug review
applications for drugs manufactured at Ranbaxy’s Paonta Sahib plant, the originally intended site of
atorvastatin manufacture. Ranbaxy has now requested permission to manufacture atorvastatin from its plant
in New Jersey (US), but it is unclear whether it will be granted. These regulatory issues have made it
uncertain whether Ranbaxy will be in a position to begin marketing atorvastatin in November 2011. Since
Ranbaxy was the first to file its application for the manufacture of generic Lipitor, the lack of a clear
regulatory decision from FDA would also prevent other generic manufacturers from manufacturing the drug.
Meanwhile, Pfizer intends to manufacture its own generic version of Lipitor, which will be distributed through
Watson Pharmaceuticals. The lack of a generic entry from other manufacturers would mean that Pfizer could
sell generic Lipitor at about 70-80% of the current Lipitor price even after the expiration of the patent
exclusivity period in November 2011. This in turn could be disadvantageous for managed care providers,
who are under pressure to contain costs.
Crestor
Scientific
Crestor (rosuvastatin calcium), a statin from AstraZeneca, registered 2010 sales of $6.7bn and holds a
market share of 22.6%. The drug is considered a preferred therapeutic option for high-risk patients owing to

60
its potency in lowering LDL-C, while raising HDL-C. In October 2009, Crestor received FDA approval for
pediatric use (patients aged 10–17 years) in treating those suffering from HeFH. This extended approval for
the drug was based on 12-week PLUTO (pediatric lipid-reduction trial of rosuvastatin) trial data. Based on
this data, the FDA also granted an additional six-month licensing exclusivity to Crestor for its approved
atherosclerosis and cholesterol indications through to July 2016. Further, in February 2010 Crestor received
FDA approval for use in the prevention of heart disease in individuals with normal LDL (low density
lipoprotein) levels and no clinically relevant heart disease in the presence of other risk factors.
In November 2007, the FDA approved Crestor for atherosclerosis, demonstrating its efficacy in slowing the
disease progression in adult patients with elevated cholesterol, as an adjunct to diet. This approval was
based on the METEOR trial data. Currently, Crestor is the only statin in the US with a broad atherosclerosis
indication.
In April 2010, the EU approved Crestor for patients with a high risk of experiencing a cardiovascular event.
The European Medicines Agency (EMA) approval followed a similar move by the FDA in 2009, and was
based on positive evidence from the 18,000-patient JUPITER trial.
Crestor has been shown to reduce LDL-C by up to 52% and raise HDL-C by up to 14% (Ridker et al., 2008).
Sales of Crestor grew over the period 2005–09, likely driven by several factors including:
new clinical data from trials such as JUPITER
expanded label approval as a result of the METEOR trial
increasing use of high potency statins
the ENHANCE and SEAS trial data that caused a shift away from Vytorin.
Clinical
JUPITER trial data released in November 2008 indicated that rosuvastatin lowered strokes and heart attacks
in people with elevated high-sensitivity C-reactive protein (hsCRP) levels, but not high cholesterol. The trial
tested Crestor versus placebo in people with low to normal LDL but an elevated hsCRP, who therefore
exhibit an increased cardiovascular risk profile.

61
AstraZeneca announced a new clinical trial for Crestor, SATURN, in January 2008. SATURN is designed to
measure the impact of 40mg Crestor and 80mg Lipitor (atorvastatin) on the progression of atherosclerosis in
high-risk patients. This study will enroll more than 1,000 patients globally and should be completed in 2011.
Data from the multinational study CORONA were presented at the AHA in November 2007. CORONA
examined the effect on cardiovascular mortality and morbidity of the addition of 10mg Crestor to optimized
treatment. It further studied overall survival from advanced heart failure in older patients who were not on
statin therapy. The study failed to show an improvement in morbidity and mortality when Crestor was added
on top of standard-of-care heart failure medication in CHF patients.
Patients who were on 10mg Crestor experienced an 8% reduction in the combined primary endpoint of
myocardial infarction or stroke, or cardiovascular death, which was statistically insignificant (Kjekshus et al.,
2007). The majority of deaths in this study were sudden, or due to non-ischemic causes, neither of which
appeared to be impacted by statin therapy.
GALAXY, a long-term global clinical research program that started in 2002, investigates the effect of Crestor
on cardiovascular risk reduction and patient outcomes. The study showed an 8% reduction in the combined
primary endpoint of myocardial infarction, stroke, or cardiovascular death, which was not statistically
significant. This reduction was driven by decreased atherosclerotic events (stroke and myocardial infarction).
Additionally, fewer hospitalizations were observed in patients on Crestor in comparison with placebo.
Furthermore, Crestor 10mg was well tolerated and had a safety profile similar to placebo. Additional clinical
trials as part of the GALAXY program are continuing and are likely to be reported in the next few years.
METEOR data indicated that Crestor slowed the progression of atherosclerosis significantly in comparison
with placebo in people who are at a lower risk of coronary heart disease and those with early signs of carotid
artery disease. Additionally, LDL-C reduced by 48.8%, in comparison with 0.3% with placebo, while HDL-C
increased by 8.0%, as against 2.8% with placebo (Crouse et al., 2007). The study met its primary endpoint,
slowing plaque progression, although treatment did not result in plaque reversal. In July 2007, Crestor
prescribing information was updated in the EU to incorporate positive atherosclerosis data from the
METEOR study.

62
In February 2010, Crestor received FDA approval for the prevention of cardiovascular disease. The drug is
now approved for use to reduce the risk of heart attack, stroke, and arterial revascularization procedures in
individuals without any clinically evident heart disease but at a high risk. This was based on the JUPITER
trial data which had shown that the disease prevention benefits of the drug outweighed the risks of adverse
effects. According to FDA documents, the drug’s wider indication is likely to increase the statin therapy target
population’s size by 15%.
Following this approval, Crestor would be the first statin for which hsCRP (high sensitivity C-reactive protein)
levels would be considered during prescribing. Individuals with hsCRP levels of greater than 2mg/L are at a
high risk of developing heart disease. In light of this expanded approval, the drug could experience higher
sales growth through 2011 until Lipitor generics reach the market. The upside for Crestor could be significant
if AstraZeneca is able to significantly promote the drug’s expanded indication with physicians as a
compound-specific advantage such that it is not viewed as a class effect.
Crestor’s US patent was upheld in June 2010 by a US district court after a trial that began in February 2010.
The challenge was raised by generic manufacturers Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and
Par on claims that the drug’s original patent filing by AstraZeneca’s partner, Shionogi, omitted material
information. This is considered to be a major victory for Crestor and is expected to provide a boost to the
overall antidyslipidemics market.
There are some concerns over the drug’s expanded approval. One of the key issues is that the expanded
patient base results are due to the inclusion of individuals with increased CRP levels (and normal LDL
levels). Elevated CRP is not a very good indicator of cardiovascular risk. Individuals who have higher than
normal CRP do have a higher risk of heart attack (as well as diseases such as cancer and diabetes), and
statins have been shown to lower circulating CRP levels. But CRP is a marker for several other indications
as well, such as arthritis, vitamin D deficiency, viral infections, and excess weight, which implies that high
CRP levels may not necessarily equate to cardiovascular risk.

63
Besides this, there are concerns about the JUPITER trial as well. In the study, 13 deaths occurred due to
gastrointestinal disorders among the Crestor group of patients (compared with one in the placebo group).
There were also 18 cases of neurocognitive dysfunction (as against four in the placebo group). Additionally,
there was a 27% rise in reported cases of diabetes in the Crestor group of patients. Based on this data, the
FDA committee had concluded that Crestor’s benefits outweighed the risks. However, diabetes itself is a risk
factor for cardiovascular disease. This further raises concern over whether Crestor could increase
cardiovascular risk in some cases.
Further to this, muscle pain is also one of the side-effects of Crestor. Therefore, if asymptomatic individuals
are given the medication only as a preventive measure, compliance is likely to be low. Appearance of any
side effects may act as a further deterrent toward compliance. There is also the question of reimbursement,
as insurers may not be keen to pay for the drug’s administration in otherwise healthy individuals. Another
question that arises is whether the ability to reduce cardiovascular risk is limited to Crestor or extends to
other statins as well (a class effect). If the effectiveness of other statins in preventing cardiovascular disease
is proved, Crestor’s commercial prospects are likely to be jeopardized. This is especially so because
generics of Merck’s Zocor (simvastatin) and Bristol-Myers Squibb’s Pravachol (pravastatin) are already
available and may encroach on Crestor sales. Another issue that plagues the drug is whether physicians
would order a CRP assay for all potential patients, as primary care physicians do not routinely screen CRP
levels.
Future blockbusters in the antidyslipidemic drug class
Lipitor was a major blockbuster drug in the cardiovascular market segment, with worldwide sales of $11.8bn
in 2010. The impending patent expiry of Lipitor is likely to impact the antidyslipidemic market severely.
Torcetrapib, developed by Pfizer, showed early promise of being a potential replacement for Lipitor.
Torcetrapib acts as an inhibitor of cholesteryl ester transfer protein (CETP) and the expectation was that this
would raise HDL levels and reduce LDL to provide improvement in cardiovascular health. However,
torcetrapib failed in Phase III clinical trials owing to an unexpected increase in cardiovascular events
associated with its use. Although this initially cast doubt on the potential for CETP inhibitors to replace
statins, extensive studies of newer lipid-lowering compounds developed by Roche and GSK show that they

Cardiac Market Outlook - 2016 by Nitesh bhele

Cardiac Market Outlook - 2016 by Nitesh bhele

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