EXECUTIVE SUMMARY
The term acute coronary syndrome (ACS) is fairly recent. Fifteen years ago, a typical textbook would have described angina pectoris, variations of classic angina such as Prinzmetal's and unstable angina, and myocardial infarction (MI, or coronary thrombosis). ACS denotes a grouping that includes unstable angina and a subclass of MI called non-Q-wave MI. This may be regarded as a relatively mild version of MI, if that is not a contradiction in terms.
This change in terminology is of more than mere academic interest; it implies a revised approach to management, in that unstable angina and non-Q-wave MI are now subject to the same broad treatment strategy. Whereas classic angina was - and still is - treated mainly with nitrates such as nitroglycerin, unstable angina is seen as a close companion and possible precursor of MI, and treated accordingly.
The definition of 'treated accordingly' is itself in a state of dynamic flux. This is a field in which different categories of drugs are known, or believed, to make a positive contribution. However, the best way of using the various classes of potentially helpful drugs is constantly under evaluation, as is the optimal combination of drugs from different classes, and relative merits of different drug candidates in each class. The present report can only aim to give an up-to-date summary of the current status of our knowledge of the best way to treat ACS, and to prevent them, both in individuals who have already suffered a crisis of this kind and in those who are at risk from coming into this category.
Four classes of drugs are discussed in detail in this report, because they are known to be helpful in ACS, even though in some cases the 'ideal drug' in its class is still being sought. In order to discuss the role of the different classes, it is necessary to put them in the context of the disease state in which they are used. Chapters 1 and 2 of the report summarise current knowledge about the nature of ACS and its treatment. Subsequent chapters deal individually with the different classes of drugs of greatest importance: antiplatelet agents, thrombolytics, anticoagulants/antithrombins and hypolipaemics. Other classes of drugs such as angiotensin-converting enzyme (ACE) inhibitors and beta-blockers also have an acknowledged role in ACS but they are not discussed in detail in this report because their primary role in medicine is as antihypertensives (although the former also has a role in heart failure). Also, nitrates are not treated in any detail because their major areas of use are in classic angina, which is not a component of ACS.
Antiplatelet drugs inhibit the aggregation of blood platelets, which is the first step in the process of thrombosis, or abnormal blood clotting within a blood vessel. These drugs are classically used in the acute situation, to prevent a thrombus forming or to inhibit further thrombi in a coronary circulation which has already suffered a thrombotic episode. Most of the widely-used drugs in this class must be given by injection (and indeed this is the preferred route in an acute emergency) but a new generation of orally-active antiplatelet agents is now in clinical research and may extend the usefulness of these drugs into the area of secondary prophylaxis.
The most widely used drugs for the prevention of ACS are the hypolipaemics; drugs which reduce blood cholesterol (especially the more harmful, low-density lipoprotein (LDL), type of cholesterol) and blood lipids generally. Elevated levels of LDL have been clearly implicated in the pathogenesis of ACS, and dietary measures alone are not always successful in reducing LDL levels. Therefore, there is an acknowledged role for hypolipaemic drugs in prophylaxis. While there is wide agreement on the need for secondary prophylaxis (to reduce the risk of further events in a patient who already has had an episode of ACS), there is an ongoing debate about the appropriate use of these and other drugs for primary prophylaxis. This entails the use of a drug or drugs to ward off ACS in someone who has not yet suffered an episode but who is deemed, from his/her medical history, to be at risk.
Anticoagulants are drugs which block the normal clotting function of the blood. They are as effective as aspirin, but much more difficult to use. They occur in nature, for example in snake venom. Leeches also produce an anticoagulant to prevent the blood, which they ingest, from coagulating. The natural anticoagulant heparin has long been used to inhibit coagulation in patients who have suffered an acute MI (AMI). It must be given by injection, and when orally-effective anticoagulants were introduced in the 1950s and 1960s it was widely hoped that they would prove to be life-saving in cases of AMI. They have not, unfortunately, fulfilled expectations, but there is an ongoing role for heparin and newer injectable anticoagulants.
While anticoagulants prevent normal blood clotting, and antiplatelets prevent abnormal clotting, or thrombosis, thrombolytic drugs act to dissolve a clot that has already formed. They are thus a treatment option for the acute stage of coronary thrombosis, when the priority is to attempt to restore the patency of the occluded blood vessel.
Surgical intervention has long been a favoured means of restoring the function of the coronary circulation when this has been interrupted by thrombosis or narrowing of one or more coronary arteries. Newer, less-invasive techniques have made surgical revascularisation a more accessible option, and these are discussed in Chapter 7; their role is usually complementary to, and not instead of, appropriate drug therapy. However studies comparing the restoration of blood vessel patency by surgical intervention and by the use of thrombolytic drugs have shown that, in some circumstances, the more conservative drug-based approach may be preferable because it is less traumatic for the patient.
Coronary heart disease (CHD) is one of the commonest causes of death, especially in the developed world. For this reason alone it would be of intense commercial interest because of the large numbers of patients who need treatment. Its potential as a source of revenue for drug manufacturers is heightened by the fact that some drugs, particularly the hypolipaemics, achieve their full potential when given long-term as a preventative strategy. This is why several drugs of this class feature among the top 100 prescription pharmaceuticals in terms of sales; Merck's Zocor was the biggest-selling prescription pharmaceutical in the world in 1997. Chapter 8 presents a review of the global and regional markets for drugs used in ACS, with an analysis of the market performance of the four major drug classes as previously defined.
The final chapter in this report (Chapter 9) presents brief profiles of companies which have major marketed drugs in the categories described above, and/or pipeline candidates which may soon become important contenders in the ACS marketplace.

CONTENTS

LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
ABBREVIATIONS

CHAPTER 1 ACUTE CORONARY SYNDROMES: DEFINITION, DIAGNOSIS AND PREVALENCE
1.1 Acute coronary syndromes: a clinical continuum
1.2 The nature of acute coronary syndromes
1.3 Ischaemic heart disease
1.4 Coronary artery disease and atherosclerosis
1.5 Acute coronary syndromes: a dynamic equilibrium
1.6 Defining the clinical spectrum
1.6.1 Angina pectoris
1.6.2 Variant angina pectoris
1.6.3 Unstable angina pectoris
1.6.3.1 Braunwald's unstable angina classifications
1.6.3.2 Common presentations of unstable angina
1.6.3.3 American Heart Association's unstable angina definitions
1.6.3.4 Angiographic findings in unstable angina
1.7 Acute myocardial infarction
1.7.1 Where to draw the diagnostic line?
1.7.2 Beyond the electrocardiogram
1.7.3 Q-wave versus non-Q-wave infarction
1.7.4 Transmural versus nontransmural infarction
1.8 Complications of acute coronary syndromes
1.9 Pathophysiology of acute coronary syndromes
1.9.1 Rethinking the pathogenesis
1.9.2 Plaque formation
1.9.3 Plaque stability and rupture
1.9.4 Platelet thrombosis
1.10 Secondary clinical causes
1.11 Risk factors
1.11.1 Genetic links in the spectrum
1.11.2 Factors affecting plaque stability
1.11.3 Baseline contributory factors
1.11.4 Factors linked to atherosclerosis
1.11.5 Age, sex and racial demographics
1.12 Epidemiology - the size of the problem
1.12.1 Mortality and severity
1.12.2 Acute coronary syndromes - clinical outcome
1.13 Recent epidemiological trends
1.14 Conclusions

CHAPTER 2 MANAGEMENT OF ACUTE CORONARY SYNDROMES
2.1 Prevention and treatment of acute coronary syndromes
2.2 Unstable angina
2.2.1 Diagnostic criteria
2.2.2 Medical treatment
2.2.3 Surgical intervention
2.3 Myocardial infarction
2.3.1 Current acute myocardial infarction care: a multifactorial approach
2.3.2 American Heart Association/American College of Cardiology recommendations
2.4 Management challenges
2.4.1 Secondary prophylaxis
2.4.2 Primary prevention
2.4.3 Maximising therapeutic potential
2.4.4 Epidemiological trends

CHAPTER 3 THROMBOLYTICS
3.1 Introduction
3.2 Products on the market
3.2.1 First generation thrombolytics
3.2.2 Second generation thrombolytics
3.3 Thrombolytics in development
3.3.1 Lanetoplase
3.3.2 TNK-tPA
3.3.3 Urokinase derivatives
3.3.4 Non-human plasminogen activators
3.4 Commercial product developments

CHAPTER 4 ANTIPLATELETS IN ACUTE CORONARY SYNDROMES
4.1 Introduction
4.1.1 Platelets and their function
4.1.2 Role of platelets in thrombosis
4.1.3 Antiplatelet agents in acute coronary syndromes
4.2 The 'standard' antiplatelet drugs
4.2.1 Aspirin
4.2.2 Ticlopidine
4.2.3 Clopidogrel
4.3 Glycoprotein IIb/IIIa receptor antagonists
4.3.1 Natural glycoprotein IIb/IIIa antagonists: disintegrins
4.3.2 Murine monoclonal antibodies
4.3.3 Synthetic peptide and non-peptide antagonists
4.4 New antiplatelet drugs in development
4.5 Current status of antiplatelet therapy
4.5.1 The cost-effectiveness issue
4.5.2 Acute versus long-term cost/benefit

CHAPTER 5 ANTICOAGULANTS AND ANTITHROMBINS
5.1 Blood coagulation
5.2 Anticoagulants
5.2.1 Heparins
5.2.2 Oral anticoagulants
5.3 Products on the market
5.3.1 Injectable anticoagulants
5.3.2 Oral anticoagulants
5.4 Heparin in acute coronary syndromes
5.4.1 Unstable angina and non-Q-wave acute myocardial infarction
5.4.2 Heparin as adjunct to thrombolysis in acute myocardial infarction
5.5 Hirudin
5.5.1 Hirudin in unstable angina pectoris
5.6 Hirulog
5.7 New thrombin antagonists
5.7.1 Argatroban
5.7.2 Inogatran
5.7.3 Efegatran
5.7.4 Corsevin M
5.7.5 LU-57291

CHAPTER 6 LIPIDS, CHOLESTEROL AND HYPOLIPAEMIC DRUGS
6.1 Introduction
6.1.1 Definitions
6.1.2 Cholesterol
6.2 Cholesterol and coronary heart disease
6.3 First generation hypolipaemic products
6.3.1 Bile acid sequestrants
6.3.2 Fibric acid derivatives
6.3.3 Nicotinic acid and derivatives
6.4 HMG CoA reductase inhibitors: the statins
6.4.1 Lovastatin
6.4.2 Simvastatin
6.4.3 Pravastatin
6.4.4 Fluvastatin
6.4.5 Other statins
6.5 Current status of the statins in hyperlipidaemia
6.6 New drugs in development
6.7 Research trends

CHAPTER 7 INTERVENTIONAL THERAPY
7.1 Overview
7.2 Angiography
7.3 Balloon angioplasty
7.3.1 Balloon catheters
7.3.2 The procedure
7.3.3 Complications
7.4 Atherectomy
7.5 Excimer laser angioplasty
7.6 Stents
7.7 Drug therapy versus revascularisation
7.8 Surgery versus angioplasty

CHAPTER 8 MARKET ESTIMATES AND TRENDS
8.1 The world pharmaceutical market
8.1.1 Market size and evolution
8.1.2 Geographical breakdown
8.1.3 Leading therapeutic categories
8.2 Cardiovascular product sector
8.2.1 Size and evolution
8.2.2 Geographical breakdown
8.2.3 Major cardiovascular product groups
8.2.4 Major cardiovascular product developments in 1998
8.3 Hypolipaemics
8.3.1 Sector size and evolution
8.3.2 Leading products and manufacturers
8.4 Antiplatelet drugs
8.4.1 Sector size and evolution
8.4.2 Leading products and manufacturers
8.5 Thrombolytics
8.5.1 Sector size and evolution
8.5.2 Leading products and manufacturers
8.6 Anticoagulants and antithrombins
8.6.1 Sector size and evolution
8.6.2 Leading products and manufacturers
8.7 Market trends
8.7.1 Demographic trends
8.7.2 Trends in medical practice
8.7.3 Research trends

CHAPTER 9 COMPANY PROFILES
9.1 Astra AB
9.1.1 Background
9.1.2 Financial results
9.1.3 Product pipeline
9.2 Boehringer Ingelheim
9.2.1 Background
9.2.2 Financial results
9.2.3 Product pipeline
9.3 Bristol-Myers Squibb
9.3.1 Background
9.3.2 Financial results
9.3.3 Product pipeline
9.4 Centocor
9.4.1 Background
9.4.2 Financial results
9.4.3 Product pipeline
9.5 COR Therapeutics
9.5.1 Background
9.5.2 Financial results
9.5.3 Product pipeline
9.6 Genentech
9.6.1 Background
9.6.2 Financial results
9.6.3 Product pipeline
9.7 Hoechst Marion Roussel
9.7.1 Background
9.7.2 Financial results
9.7.3 Product pipeline
9.8 Merck
9.8.1 Background
9.8.2 Financial results
9.8.3 Product pipeline
9.9 Novartis
9.9.1 Background
9.9.2 Financial results
9.9.3 Product pipeline
9.10 Pfizer
9.10.1 Background
9.10.2 Financial results
9.10.3 Product pipeline
9.11 Roche
9.11.1 Background
9.11.2 Financial results
9.11.3 Product pipeline
9.12 Sanofi
9.12.1 Background
9.12.2 Financial results
9.12.3 Product pipeline
9.13 Schering AG
9.13.1 Background
9.13.2 Financial results
9.13.3 Product pipeline
9.14 SmithKline Beecham
9.14.1 Background
9.14.2 Financial results
9.14.3 Product pipeline
9.15 Warner-Lambert
9.15.1 Background
9.15.2 Financial results
9.15.3 Product pipeline
9.16 Zeneca
9.16.1 Background
9.16.2 Financial results
9.16.3 Product pipeline

BIBLIOGRAPHY

LIST OF TABLES
Table 1.1 Braunwald's classification of unstable angina
Table 1.2 Braunwald patient classification findings from the GUARANTEE Study
Table 1.3 Baseline characteristics of patients with ACS in GUSTO IIb

Table 2.1 Aspirin in unstable angina
Table 2.2 TIMI IIIB: results at six weeks
Table 2.3 Predictors of recurrent CHD
Table 2.4 Risk factors preventable by lipid-lowering treatment

Table 3.1 Thombolytics in clinical development

Table 4.1 Orally-effective antiplatelet drugs in clinical development

Table 6.1 Hypolipaemics in clinical development

Table 8.1 Major drug classes used in ACS: 1997 sales and growth
Table 8.2 Hypolipaemic products: 1997 global sales, with annual growth figures
Table 8.3 Marketed antiplatelet drugs; 1997-1998; sales and growth over 1996
Table 8.4 Leading thrombolytic products, 1997
Table 8.5 Leading anticoagulant products, 1997

Table 9.1 Astra: five-year financial figures
Table 9.2 Boehringer Ingelheim: five-year financial figures
Table 9.3 Bristol-Myers Squibb: five-year financial figures
Table 9.4 Centocor: five-year financial figures
Table 9.5 Genentech: five-year financial figures
Table 9.6 Hoechst Group: five-year financial figures
Table 9.7 Merck & Co: five-year financial figures
Table 9.8 Novartis: financial figures
Table 9.9 Pfizer: five-year financial figures
Table 9.10 Roche: five-year financial figures
Table 9.11 Sanofi: five-year financial figures
Table 9.12 Schering AG: five-year financial figures
Table 9.13 SmithKline Beecham: five-year financial figures
Table 9.14 Warner-Lambert: financial figures
Table 9.15 Zeneca: five-year financial figures

LIST OF FIGURES
Figure 1.1 Overview of complications of myocardial infarction

Figure 2.1 Thrombolytic therapy intervention

Figure 8.1 Growth of the world pharmaceutical market, 1993-1998
Figure 8.2 Division of the global pharmaceutical market by region
Figure 8.3 Geographical breakdown of cardiovascular product sales, developed world markets, 1997
Figure 8.4 WHO estimates of life expectancy (both sexes, in years)
Figure 8.5 Future pattern of drug therapy for ACS

Publication: January 1999
Ref: BS976E
Pages: 150
Price: £495/$1,040/¥119,000

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