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Greenhalgh J, Bagust A, Boland A, et al. Clopidogrel and Modified-Release Dipyridamole for the Prevention of Occlusive Vascular Events (Review of Technology Appraisal No. 90): A Systematic Review and Economic Analysis. Southampton (UK): NIHR Journals Library; 2011 Sep. (Health Technology Assessment, No. 15.31.)

1Background

Description of the health problem

Cardiovascular disease' is an umbrella term that includes coronary heart disease, peripheral arterial disease and cerebrovascular disease. Cardiovascular disease is commonly caused by arteries becoming narrowed through atherosclerosis; it is the main cause of death in the UK, accounting for 35% of deaths each year (almost 198,000).1 Almost half (48%) of all cardiovascular disease deaths are from coronary heart disease, with stroke making up a further quarter (28%).1 In addition to being the main cause of death, cardiovascular disease is also the major cause of premature death (< 75 years) in the UK; cardiovascular disease caused 30% of premature death in men and 22% in women in 2006.1

Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are classified as subsets of cardiovascular disease. These events are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Patients with a history of such events have an increased risk of recurrence when compared with the general population. Peripheral arterial disease is also a subset of cardiovascular disease and is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. Patients with symptomatic peripheral arterial disease (typically intermittent claudication) are at increased risk of experiencing an initial occlusive vascular event. Given the nature of the health problem, some people have what is classified as multivascular disease, i.e. disease in more than one vascular bed, and appear to be at an even greater risk of death, MI or stroke than those with disease in a single bed.2 Therefore, the primary objective in the treatment of all patients with a history of cardiovascular disease is to prevent the occurrence of new occlusive vascular events.

Aetiology, pathology and prognosis

As noted earlier, the cause of occlusive vascular events is a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Atherothrombosis involves the formation of a platelet-rich thrombus, frequently at the site of a disrupted atherosclerotic plaque, that leads to local occlusion or distal embolism. Atherosclerotic plaque formation occurs as a result of damage to vascular endothelium. Possible causes of damage include the following: elevated and modified low-density lipoproteins; free radicals caused by cigarette smoking, hypertension and diabetes mellitus; genetic alterations; and, combinations of these and other factors.3

Epidemiology

The five manifestations of cardiovascular disease considered in this report are MI, ischaemic stroke, TIA, peripheral arterial disease and multivascular disease.

Myocardial infarction

Myocardial infarction (also known as a heart attack) is the interruption of the blood supply to the heart muscle. This is most commonly caused by occlusion of a coronary artery following the rupture of an atherosclerotic plaque. The resulting restriction in blood supply and oxygen starvation can cause damage to, or the death of, the heart muscle. Typical symptoms of MI include sudden chest pain with sweating or nausea, but MIs can also be symptomless. Women may experience different symptoms to men. Based on the results of changes in electrocardiogram (ECG) readings, MIs are classified into two subtypes: non-ST-segment elevated MI (NSTEMI) or ST-segment elevated MI (STEMI). The distinction has implications for future antiplatelet treatment. After a MI, a patient remains at high risk of a further MI or other occlusive vascular event.

Data from 2006 for the UK demonstrate that, across all ages, there were 146,000 cases of MI: 87,000 in men and 59,000 in women.1 The incidence of MI varies across regions, between men and women, and increases with age.1 Higher incidence rates are apparent in northern areas of the UK than in southern areas. In the UK, among men and women aged > 35 years, the prevalence is thought to be over 1.4 million.1 Approximately 30% of people who experience an acute MI die before they reach hospital.4 Patients who experience a MI and survive are likely to have a further cardiac event.5

Ischaemic stroke

There are a number of different types of stroke; however, the majority of cases (approximately 70%) are ischaemic, caused through the blockage of an artery in the brain.6 This leads to damage to, or death of, the brain cells due to lack of oxygen. The symptoms of stroke can include: numbness, weakness or lack of movement on one side of the body, slurred speech, difficulty finding words or understanding speech, problems with vision, confusion and/or severe headache.7 A stroke happens suddenly and the effects are experienced straight away.7 Anyone who suddenly has symptoms that might be caused by a stroke should be assessed as soon as possible using a test such as FAST (Face, Arm, Speech Test) and, on arrival at hospital, the ROSIER (Recognition of Stroke in the Emergency Room) test may be used.7 A stroke may be classified as disabling or non-disabling.

The British Heart Foundation (BHF) reports that approximately 98,000 people experience a first ischaemic stroke every year in the UK, with little difference in rates between men and women but an increased risk with age.8 Additionally, they estimate from 2006 data that, in the UK, as many as 1.1 million people have experienced a stroke; this is equivalent to a prevalence rate of 1.6% in the population in England and 2% in Wales.8 The risk of recurrent stroke is greatest in the first 6 months following the initial event, but a patient may remain at greater risk of stroke than the general population for a number of years.3 As many as 30% of strokes are thought to be recurrent.9 Patients who have experienced a stroke are also at risk of further occlusive vascular events, including MI.10,11

Transient ischaemic attack

A TIA is a disorder caused by temporary disturbance of blood supply to an area of the brain that results in a sudden but brief decrease (< 24 hours, usually < 1 hour) in brain functions and causes stroke-like symptoms. If the neurological deficit lasts more than 24 hours it is described as a stroke. Estimates for the UK indicate that between 46,000 and 65,000 people suffer a TIA each year and prevalence of TIA is projected to be 510,000.8 In contrast with the trend noted in stroke data, there appear to be higher rates of TIA in women, and, as noted for stroke, incidence and prevalence rates increase rapidly with age.8 Patients experiencing a TIA are at high risk of suffering a subsequent stroke, with 90-day risks of stroke reported to be as high as 10.5%.12 In patients enrolled in clinical trials after a TIA or non-disabling ischaemic stroke, the annual risk of important vascular events (death from all vascular causes, non-fatal stroke or non-fatal MI) is reported as being between 4% and 11%; the corresponding estimate for population-based studies is 9% per year.13

Peripheral arterial disease

Peripheral arterial disease is a condition in which the arteries that carry blood to the arms or legs become narrowed or congested, slowing or stopping the flow of blood. Data related to the prevalence of peripheral arterial disease vary. Detailed data from the USA indicate peripheral arterial disease rates of 4.3% in those < 40 years of age and 14.5% in those > 75 years.14 Other reports estimate rates at 12–14% in the general population and 20% in those > 75 years of age.15 The scoping document for this review indicated that, for the UK, approximately 20% of people aged from 55 to 75 years of age have evidence of lower extremity peripheral arterial disease and 5% of these appear to have symptoms, the most common of which is intermittent claudication (pain on walking). As the size of the UK population aged ≥ 55 years is approximately 17 million, this equates to a prevalence of around 170,000 with intermittent claudication.16 It is thought that worldwide, and in the UK, peripheral arterial disease is underdiagnosed and undertreated.17,18 Patients with peripheral arterial disease may experience significant pain and poor quality of life (QoL).19 Over 5 years, about 20% of people with intermittent claudication have a non-fatal cardiovascular event (MI or stroke).15 People with peripheral arterial disease, including those who are asymptomatic, have a high risk of death from MI and ischaemic stroke, their relative risks (RRs) being two to three times that of age- and gender-matched groups.19 coronary heart disease is the major cause of death in people with peripheral arterial disease of the legs.20

Although the diagnosis of peripheral arterial disease can generally be made from clinical history and examination, objective evidence of significant peripheral arterial disease can be made by obtaining an ankle–brachial pressure index. This index is the ratio of the ankle to brachial systolic pressure and may be measured using a sphygmomanometer and handheld Doppler device.19 Obtaining an ankle–brachial pressure index is non-invasive and relatively easy, but is rarely used in clinical practice.21

Multivascular disease

As noted earlier, there are a number of patients with cardiovascular disease who have disease in more than one vascular bed (otherwise known as multivascular disease patients). The REACH registry (supported by Sanofi–aventis, Bristol–Myers Squibb and the Waksman Foundation) collected data from approximately 67,888 patients who were recruited from 5473 physician practices in 44 countries worldwide.17,22 Patients in the registry are described as being > 45 years old with least three atherothrombotic risk factors (e.g. treated diabetes mellitus, diabetic nephropathy, ankle–brachial index < 0.9, asymptomatic carotid stenosis of ≥ 70%) or documented cerebrovascular disease, coronary artery disease or peripheral arterial disease. A survey22 of data from the REduction of Atherothrombosis for Continual Health (REACH) registry identified that 15.9% of patients had symptomatic polyvascular disease, defined as coexistent symptomatic (clinically recognised) arterial disease in two or three territories (coronary, cerebral and/or peripheral). A further analysis indicated that rates of cardiovascular death, MI or stroke at 1 year increase substantially with the number of affected vascular beds.2 This recognition of the importance of multivascular disease, problems with its definition, and its inherent increased risk of further events is explored in Chapter 3 (see Patients with multivascular disease).

Trends in coronary heart disease and stroke

Coronary heart disease causes over 90,000 deaths a year in the UK: approximately one in five deaths in men and one in six deaths in women. There is geographical variation in prevalence, with greater rates in the northern areas of England than in southern areas and intermediate rates in Wales. There are also social inequalities in mortality from coronary heart disease: higher mortality is noted in people from more deprived areas and those working in manual jobs.1

Death rates from coronary heart disease have been declining since the late 1970s and death rates from stroke have declined in the last 10 years, although these trends appear to be plateauing, particularly in younger people. It is thought that the decline in rates of coronary heart disease is owing to reductions in risk factors (mainly smoking) and better treatment (including secondary prevention). Although mortality appears to be falling, coronary heart disease-related morbidity is rising.1

Stroke accounts for around 53,000 deaths each year in the UK (approximately 9% of all deaths). According to the BHF8 it is not possible to know how many deaths each year are attributable to each stroke subtype. However, it reports that age-standardised mortality rates from stroke have decreased markedly in the last four decades, with a 90% reduction in ischaemic stroke mortality.8 There is geographical variation in death rates from stroke in the UK; the highest rates are in Scotland, followed by northern England, Wales and Northern Ireland. The south of England (particularly London) exhibits the lowest stroke mortality rates. Socioeconomic inequalities in stroke mortality are evident; historically, rates have decreased more quickly in adults from higher social classes and mortality increases with deprivation.8

The majority of people survive an initial stroke, but often have significant morbidity.7 Stroke causes a greater range of disabilities than any other condition and has a greater disability impact than other chronic diseases.23 It is thought that more than 900,000 people in England are living with the effects of stroke, with half of these being dependent on other people for help with everyday activities.7

Impact of health problem

In 2006–7 there were 428,000 inpatient episodes for coronary heart disease in England and over 175,000 for stroke.1,8 Data from 2006 underline the high cost of coronary heart disease and stroke to the UK health-care system: each cost around £3.2B. A cost per capita of just over £50 for each condition was observed.1 Hospital care costs for coronary heart disease accounted for 73% of the total cost, whereas for stroke hospital costs accounted for 94%.1

Production losses from death and illness and from informal care of people with coronary heart disease and cardiovascular disease are a substantial financial burden.1 Data from 2006 for the UK demonstrate that production losses owing to mortality and morbidity associated with coronary heart disease cost over £3.9B: 65% owing to death and 35% owing to illness in those of working age. Informal care costs were approximately £1.8B.1 For stroke, 65% of production losses were owing to illness and costs of informal care were £2.9M, reflecting the debilitating impact of stroke on individuals.1

Current service provision

Management of disease

Secondary prevention of occlusive vascular events is antiplatelet therapy. Current recommendations from the National Institute for Health and Clinical Excellence (NICE) in Technology Appraisal No. 90 (TA90)24 for the secondary prevention of occlusive vascular events in patients with a history of ischaemic stroke or TIA state that modified-release dipyridamole (MRD) in combination with acetylsalicylic acid [ASA (aspirin)] should be used for a period of 2 years from the most recent event. Thereafter, or if MRD is not tolerated, standard care (including long-term, low-dose ASA) should be used. People with a history of occlusive vascular events (except TIA) or peripheral arterial disease who are intolerant to low-dose ASA are advised to use clopidogrel (clopidogrel) alone.

Owing to the evolving nature of treatments, and the different patient groups included in this review, a number of clinical recommendations are relevant. These are described in Table 1.

TABLE 1. Patient populations and clinical recommendations.

TABLE 1

Patient populations and clinical recommendations.

In addition to TA90,24 there are separate (and different) clinical recommendations for the two subtypes of MI: NSTEMI and STEMI. Clopidogrel plus ASA is the recommended treatment for both types, but for a period of 12 months following a NSTEMI25 and 4 weeks in the event of a STEMI. There is currently no guidance for the prevention of occlusive vascular events in patients with multivascular disease.

The purpose of the current review is to update the evidence base that was available to inform NICE's TA90 guidance.3,24 Patient groups who are beyond its remit include those who have had, or are at risk of, a stroke associated with atrial fibrillation or who require treatment to prevent occlusive vascular events after coronary revascularisation or carotid artery procedures.

Although explicit data on provision of antiplatelet treatment for patients in the various disease categories are not available, general practitioner (GP) prescribing data for England from 2004 to 200931 indicate a slow and steady increase in prescribing rates over that time period (Figure 1).

FIGURE 1. Trends in prescribing of antiplatelet drugs in general practice in England.

FIGURE 1

Trends in prescribing of antiplatelet drugs in general practice in England. Reproduced with permission from the NHS Business Services Authority (NHSBSA).

Current service cost

The current prices for ASA, MRD and clopidogrel are shown in Table 2. All prices are net and are taken from the British National Formulary (BNF) No. 58.32 Generic versions of clopidogrel are now licensed; from 1 April 2010, clopidogrel is listed as category M of Part VIII of the Drug Tariff, meaning that pharmacists will be reimbursed at the generic price of £10.90 for 30 tablets of 75 mg clopidogrel.33,34

TABLE 2. Prices of ASA, MRD and clopidogrel.

TABLE 2

Prices of ASA, MRD and clopidogrel.

In Figure 2, trends in spending on the various agents prescribed by GPs in England over the period of 2004–9 are shown.31

FIGURE 2. Trends in spending on antiplatelet drugs in general practice in England.

FIGURE 2

Trends in spending on antiplatelet drugs in general practice in England. Reproduced with permission from the NHSBSA. NIC, net ingredient cost.

Variation in services and/or uncertainty about cost

The recent end of patent term for clopidogrel has meant that a number of generic formulations of the drug have been approved by the European Medicines Agency35 and the Medicines and Healthcare products Regulatory Agency (MHRA).36 At the time of writing, there are at least eight generic products available in the UK, as listed in Table 3. All of those listed are licensed for the prevention of atherothrombotic events in patients suffering from MI (from a few days until < 35 days), ischaemic stroke (from 7 days until < 6 months) or established peripheral arterial disease. It is currently unclear (because of issues relating to patent) whether or not any of these products may also be used in combination with ASA for the treatment of patients with acute coronary syndromes.

TABLE 3. Generic versions of clopidogrel available in the UK.

TABLE 3

Generic versions of clopidogrel available in the UK.

Relevant national guidelines including National Service Frameworks

The design of guidelines and National Service Frameworks (NSFs) is based on overall national goals and targets. The government target for England (set in 1999 and 2004) for cardiovascular disease was to reduce the death rate from coronary heart disease, stroke and related diseases in people aged ≤ 75 years by at least two-fifths by 2010, saving up to 200,000 lives in total, with a milestone of a reduction of one-quarter by 2005.37,38 A further target was to reduce the inequalities gap in death rates from these diseases between the fifth of areas with the worst health and deprivation indicators and the population as a whole in people aged ≤ 75 years by 40% by 2010.

The Welsh Assembly Government39,40 set its target for coronary heart disease as a reduction in mortality rates in 65- to 74-year-olds from 600 per 100,000 in 2002 to 400 per 100,00 in 2012. Its health inequality target is to improve coronary heart disease mortality in all groups and at the same time aim for a more rapid improvement in the most deprived groups. The target for stroke is to reduce mortality in people aged 65–74 years by 20% by 2012.

New GP contracts include points for the number of coronary heart disease and stroke patients who are taking antiplatelet therapy for secondary prevention of occlusive vascular events.41 The contract does not appear to include patients with peripheral arterial disease.42

Therefore, the use of antiplatelet agents is the focus of a number of national documents including the National Service Framework43,44 and NICE guidance documents.25,45 The nature of multivascular disease means that at times these documents apply to overlapping patient populations.

The National Service Framework (NSF) for Coronary Heart Disease: Standards and Quality Requirements (England) states that GPs and primary care teams should identify all patients with established cardiovascular disease and offer them comprehensive advice and appropriate treatment to reduce their risks of coronary heart disease.43,44

The National Stroke Strategy: Ten Point Plan for Action for England states that in preventing stroke, support for healthier lifestyles should be offered and action to tackle vascular risk taken.46

As part of the Diabetes, Heart Disease and Stroke (DHDS) prevention project, the UK National Screening Committee commissioned the Handbook of vascular risk assessment, risk reduction and risk management.47 The handbook is designed to support local health services in meeting the standards for the prevention and early detection of coronary heart disease, set out in the NSF for England. The target population for screening is people aged between 40 and 75 years. The handbook describes the context and outlines evidence for a coordinated vascular disease control programme to identify and reduce risks of cardiovascular disease in the general population; suggest aims, objectives and a delivery strategy framework appropriate for a cardiovascular disease risk management programme; report key messages from the DHDS pilot project; and provide examples of tools, resources and standard operating procedures that can be used by health professionals.47

Description of technology under assessment

Two antiplatelet agents, used within their licensed indications, are the focus of this review: clopidogrel® (Plavix®, Bristol–Myers Squibb, Sanofi–aventis) and MRD + ASA in a single capsule (Asasantin Retard®, Boehringer Ingelheim) or MRD alone (Persantin Retard®, Boehringer Ingelheim). Clopidogrel produces an immediate and sustained inhibition of ADP-induced platelet aggregation that helps prevent blood clots.48 Dipyridamole is thought to inhibit adenosine (a potent inhibitor of platelet activation and aggregation) uptake into blood and vascular cells.3 Summaries of product characteristics for clopidogrel, MRD + ASA and MRD alone are available from the Electronic Medicines Compendium.49

Clopidogrel

Clopidogrel is licensed in adults for the prevention of atherothrombotic events in patients suffering from MI (from a few days to 35 days), ischaemic stroke (from 7 days to 6 months) or established peripheral arterial disease. Clopidogrel is available as 75 or 300 mg film-coated tablets. The recommended dose is 75 mg as a single daily dose, taken with or without food. As previously noted, generic versions of clopidogrel are now available (see Table 3), although it is currently unclear whether or not any of these generic versions are licensed for prescribing with ASA for the treatment of acute coronary syndromes

Contraindications for clopidogrel include hypersensitivity to the active substance or to any of the excipients, severe liver impairment and active pathological bleeding (such as a peptic ulcer or intracranial haemorrhage). Special warnings for clopidogrel use include (but are not limited to) the following:

Based on literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates after MI than do patients with normal CYP2C19 function. As clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 should be discouraged. Although the evidence of CYP2C19 inhibition varies within the class of proton pump inhibitors (PPIs), clinical studies suggest an interaction between clopidogrel and possibly all members of this class. Therefore, concomitant use of PPIs should be avoided unless absolutely necessary. The Assessment Group is aware that new evidence has led to a new recommendation from the European Medicines Agency50 that only two specific PPIs (omeprazole and esomeprazole) are a problem (see below).

Important subgroups of patients

Clopidogrel is not licensed for secondary prevention of occlusive vascular events in patients who have experienced a TIA, although in UK clinical practice it may be prescribed for these patients if they are unable to tolerate MRD or ASA (Dr Anil Sharma, Aintree Hospitals NHS Trust, 17 March 2010, personal communication).

There is evidence that two PPIs (omeprazole and esomeprazole) reduce the effectiveness of clopidogrel in preventing the recurrence of adverse cardiac events; current advice is that concomitant use of these with clopidogrel should be discouraged. In addition, the concomitant use of other known CYP2C19-inhibiting medicines with clopidogrel is discouraged because these are expected to have a similar effect to omeprazole and esomeprazole.50

Modified-release dipyridamole

A non-modified-release (often referred to as immediate release) version of dipyridamole is available; however, only the evidence for MRD is considered in this review. MRD is often also referred to as an ‘extended-release dipyridamole’. For clarity, this review will use the term MRD throughout.

Modified-release dipyridamole (alone or with ASA) is licensed for use in adults for the secondary prevention of ischaemic stroke and TIA. It is available in two preparations:

  • Asasantin Retard® (Boehringer Ingelheim) capsules containing both dipyridamole (200 mg) and ASA (25 mg).
  • Persantin Retard® (Boehringer Ingelheim) capsules containing dipyridamole (200 mg).

The recommended dose of MRD is 200 mg twice daily. Capsules should be taken in the morning and again in the evening, preferably with meals.

Contraindications for Asasantin Retard® include hypersensitivity to any component of the product or salicylates, patients with active gastric or duodenal ulcers, and patients in the last trimester of pregnancy. Special warnings and precautions for use include (but are not limited to):

  • Asasantin® should be used with caution in patients with an increased risk of bleeding and such patients should be followed carefully for any signs of bleeding.
  • Caution should be advised in patients receiving concomitant medication that may increase the risk of bleeding.
  • Headache that may occur at the beginning of treatment should not be treated with analgesic doses of ASA.
  • Among other properties, dipyridamole acts as a vasodilator. It should be used with caution in patients with severe coronary artery disease, including unstable angina or recent MI, left ventricular flow obstruction or haemodynamic instability.
  • Owing to the ASA component, all appropriate cautions applicable to ASA should also be observed.

Contraindications for Persantin Retard® are limited to hypersensitivity to any component of the product. The same cautions should be observed as for Asasantin Retard® (with the exception of those related to the ASA content).

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Clopidogrel and Modified-Release Dipyridamole for the Prevention of Occlusive Vascular Events (Review of Technology Appraisal No. 90): A Systematic Review and Economic Analysis
Clopidogrel and Modified-Release Dipyridamole for the Prevention of Occlusive Vascular Events (Review of Technology Appraisal No. 90): A Systematic Review and Economic Analysis.
Health Technology Assessment, No. 15.31.
Greenhalgh J, Bagust A, Boland A, et al.
Southampton (UK): NIHR Journals Library; 2011 Sep.

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