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- 1. Peripheral Arterial Disease (PAD) A marker for myocardial infarction and ischaemic stroke
- 7. Atherothrombosis – coexistence of symptomatic PAD and coronary or cerebrovascular disease Percentage of group Concurrent cardiovascular disease (MI, CABG, stroke or stroke surgery) PAD No 0 10 20 30 40 50 Men Women Yes Yes No Criqui MH et al. Vasc Med 1997;2:221–226.
- 8. Atherothrombosis – symptomatic atherosclerosis in CAPRIE (overlap between PAD, CAD and CVD) 1 CAPRIE Steering Committee. Lancet 1996;348:1329–1339. CAPRIE 1 ( n = 19 185) Cerebrovascular disease (CVD) Peripheral Arterial Disease (PAD) Coronary artery disease (CAD) 24.6% 29.9% 19.2% 3.3% 3.8% 7.3% 11.9%
- 9. Patients with PAD are at risk of MI, IS and death CAPRIE data Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1–128 (Abstr 4). 0 1 2 3 4 5 6 3-year cumulative event rate (%) Clopidogrel Aspirin 4.2 5.1 3.6 5.2 Patients qualifying for CAPRIE on the basis of PAD Coronary outcome Cerebrovascular outcome
- 10. 5-year natural history of PAD 100 patients with asymptomatic PAD 100 patients with claudication who do not seek medical advice Local Events 100 patients diagnosed with claudication Systemic Events • CHD 15 • Other cardiovascular and cerebrovascular 5 • Non-cardiovascular 10 PLUS Major amputation 2 patients 10 to 20 non-fatal MIs or strokes Dormandy JA. Hosp Update 1991;April:314–318. 30 deaths: Surgical revascularization 10 patients Worsening claudication 25 patients
- 11. PAD mortality – 10-year survival rates of subjects in the San Diego Artery Study Criqui MH et al. N Engl J Med 1992;326:381–386. Time (years) 0 2 4 6 8 10 12 0.00 0.25 0.50 0.75 1.00 Survival Severe symptomatic Symptomatic Asymptomatic Normal
- 12. Relative 5-year PAD mortality rates versus other common pathologies 1 American Cancer Society. Cancer Facts and Figures – 1997. 2 Kampozinski RF, Bernhard VM. In: Vascular Surgery (Rutherford RB, ed). Philadelphia, PA: WB Saunders: 1989;chap 53. 15 18 28 38 86 0 10 20 30 40 50 60 70 80 90 100 Breast cancer 1 Hodgkin's disease 1 PAD 2 Colon and rectal cancer 1 Lung cancer 1 Patients (%)
- 15. ABPI – inverse relationship with 5-year risk of cardiovascular events and death Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1–128 (Abstr 4). 10.2% relative risk increase per 0.1 decrease in ABPI ( p = 0.041) Risk relative to ABPI 1.0 0.8 0.6 0.4 0.2 0.0 1.0 1.5 2.0 2.5 ABPI
- 22. 1 CAPRIE Steering Committee. Lancet 1996;348:1329–1339. 2 Antiplatelet Trialists' Collaboration. BMJ 1994;308:81–106. 3 Fisher LD. J Am Coll Cardiol 1998;31(Suppl A):49A. CAPRIE – efficacy profile of clopidogrel Time from Randomization (Months) Event rate/1000 patients/year 0 3 6 9 12 15 18 21 24 27 30 33 36 Event rate per year Placebo 3 * Aspirin 1 Clopidogrel 1 7.7% 5.8% 5.3% * extrapolated curve 3 Based on the APTC findings, 2 in a population similar to CAPRIE, for each 1000 patients treated per year, aspirin can be expected to prevent 19 events and clopidogrel, 24. 1 0 40 80 120 160 8.7% relative risk reduction, p = 0.043 58 77 53 24 19
- 23. CAPRIE – safety profile of clopidogrel 1 CAPRIE Steering Committee. Lancet 1996;348:1329–1339; 2 Bogousslavsky J. Cerebrovasc Dis 1998;8(Suppl 4):43; 3 Lok DJA. Eur Heart J 1998;19(Abstract Suppl):52. * The proportions of patients with diarrhoea, rash or pruritus were higher in the clopidogrel group than in the aspirin group 0 50 100 150 200 250 300 GI haemorrhages Hospitalization for GI bleeding events GI ulcer Clopidogrel Aspirin Number of Patients 71 191 37 P < 0.05 P < 0.05 P < 0.01 104 255 51
Notas do Editor
- Title slide
- Overview This slide provides an overview of the presentation. The initial two slides introduce peripheral arterial disease (PAD) as one of several manifestations of atherothrombosis. The major part of the presentation provides an overview of epidemiological data on PAD, describing: risk factors and prevalence of PAD; atherothrombosis (coexistence of coronary and cerebrovascular disease); the natural history of PAD; evidence for PAD as a risk factor for ischaemic stroke (IS), myocardial infarction (MI) and all-cause mortality; and the inverse relationship between ankle:arm blood pressure index (ABPI) and risk of IS, MI and mortality. The symptomatology, diagnosis and management of PAD is outlined, including the rationale for the use of antiplatelet agents in PAD patients. The final section describes the overall benefit of clopidogrel in preventing major vascular ischaemic events (IS, MI, vascular death) in atherothrombotic patients, including those with diagnosed PAD.
- PAD – a marker for MI and IS Atherothrombosis is a generalized process that occurs throughout the arterial tree. Peripheral arterial disease (PAD) is one of several manifestations of atherothrombosis. This process occurs when a platelet-rich clot (thrombus) forms at the site of an unstable or disrupted atherosclerotic plaque. In the brain, atherothrombosis may result in transient ischaemic attack or ischaemic stroke. In the coronary arteries it can lead to stable or unstable angina, and in the peripheral arteries atherothrombosis causes leg-muscle ischaemia (varying from asymptomatic to severe symptomatic disease). PAD can be asymptomatic (pre-existing atherosclerosis as a diffuse marker of the disease, placing patients at risk of an ischaemic event elsewhere in the vasculature) or symptomatic (intermittent claudication, critical leg ischaemia).
- Risk factors for PAD As would be expected, the risk factors for PAD are similar to those for atherosclerosis affecting the heart and brain. These risk factors include those related to lifestyle, such as smoking, diet and physical inactivity. 1 Common conditions such as diabetes 1 and hypertension 1 are also associated with increased risk of PAD. The role of infection in the development of atherosclerosis is currently the focus of much interest. 2 Homocysteinaemia, 3 hypercholesterolaemia 1 and hypercoagulable states 4 also increase the risk of vascular disease. Thus, factors that can be controlled, such as diet and smoking, and factors that cannot be altered, such as genetic traits, gender, 1 and age, 1 are all known to be associated with increased risk of PAD. 1,2 Although there are similarities in risk factors for atherosclerosis throughout the vasculature, the degree of risk associated with a given risk factor may differ for each arterial bed. For example, smoking and diabetes are widely held to be the strongest risk factors for PAD. PAD patients are at high risk of ischaemic events, as PAD is a risk marker for MI and stroke. 1 Murabito JM, D’Agostino RB, Silbershatz H et al . Intermittent claudication. A risk profile from the Framingham Heart Study. Circulation 1997;96:44–49. 2 Laurila A, Bloigu A, Nayha S et al . Chronic Chlamydia pneumoniae infection is associated with a serum lipid profile known to be a risk factor for atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:2910–2913. 3 Malinow MR, Kang SS, Taylor LM et al . Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989;79:1180–1188. 4 Brigden ML. The hypercoagulable state: who, how, and when to test and treat. Postgrad Med 1997;101(5):249–262.
- Prevalence of PAD – variation according to diagnostic criterion Estimates of PAD prevalence vary according to which definition of PAD is used. In the USA and the EU, 6.3 million people are currently diagnosed as having established, symptomatic PAD. 1 However, the actual number of individuals with PAD in the USA and EU may be three times as high as the number of individuals actually diagnosed with the disease. In a study 2 of a free-living population of 613 men and women, mean age 66 years, intermittent claudication – defined as either classic intermittent claudication or any exercise calf pain – underestimated the prevalence of ‘real’ PAD, as assessed by non-invasive testing (ankle:brachial pressure index [ABPI] and posterior tibial flow velocity). Thus, real PAD was about two to seven times more common than a history of intermittent claudication would suggest. Conversely, the presence of one or more abnormal peripheral pulses tended to overestimate the prevalence of real PAD by a factor of two. ABPI alone has been shown to correlate highly ( r = –0.731) with angiographically determined disease in a series of PAD patients. 2 A recent study validated the use of ABPI to screen for atherosclerosis. 3 A low ABPI identified patients with increased risk. ABPI < 0.9 (abnormal pulse) is a marker of atherothrombosis . 4 It is not systematically correlated with the presence of symptoms. ABPI measurements can be conducted at low cost, using simple techniques, and are non-invasive. 1 17 Western European countries. American Heart Association Heart & Stroke Facts: 1997 Statistical Supplement; WHO Yearbooks, Annual Statistics, 1997. 2 Criqui MH, Denenberg JO, Langer RD et al . The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997;2:221–226. 3 Shinozaki T, Hasegawa T, Yano E. Ankle–Arm Index as an indicator of atherosclerosis: its application as a screening method. J Clin Epidemiol 1998;15:1263–1269. 4 Kornitzer M, Dramaix M, Sobolski J et al . Ankle/arm pressure index in asymptomatic middle-aged males: an independent predictor of ten-year coronary heart disease mortality. Angiology 1995;46:211 – 219.
- Epidemiology of PAD – effect of age and gender There are fewer epidemiological data on PAD than there are on myocardial infarction and stroke. Existing data show variations depending on the populations being studied and the diagnostic methods employed. However, general features of the epidemiology of PAD can be summarized as follows:(i) the increase and prevalence of PAD increase with age; (ii) PAD is more common in men than it is in women; (iii) the predominance of PAD in males diminishes in those aged > 70 years. 1 1 Weitz JI, Byrne J, Clagett GP et al . Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation 1996;94:3026–3049.
- Atherothrombosis – coexistence of PAD and symptomatic coronary or cerebrovascular disease The findings of a number of epidemiological studies support the concept that PAD reflects more widespread atheromatous disease. The San Diego Artery Study, 1 in which an ankle-brachial pressure ratio (ABPR) of < 0.8 was used as a marker for PAD, assessed how often PAD occurred in association with other manifestations of atherosclerosis. Among men with PAD, 29.4% had cardiovascular disease (CVD; either CHD, defined as previous MI or bypass surgery, or cerebrovascular disease, indicated by a previous stroke or stroke-related surgery). Among women with PAD, 21.2% had CVD. In comparison, 11.5% of men and 9.3% of women without PAD had a history of CVD. Thus, in this study, other CVD occurred two to three times more frequently among persons with PAD. 1 Criqui MH, Denenberg JO, Langer RD et al . The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997;2:221–226.
- Atherothrombosis – symptomatic atherosclerosis in CAPRIE (overlap between PAD, CAD and CVD) Substantial evidence on the coexistence of atherothrombotic disease comes from a large, prospective trial of patients with symptomatic atherosclerosis. By design, the CAPRIE 1 trial enrolled approximately equal numbers of patients (mean age 62.5 years) to three groups defined by the following qualifying conditions: recent IS, recent MI or established PAD. As atherothrombosis is a generalized condition that can develop throughout the vasculature, it is not surprising that 26.3% of the total study cohort were found to have atherothrombosis affecting one or two other vascular beds. 1 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
- Patients with PAD are at risk of MI, IS and death Patients with symptomatic atherosclerotic PAD are at risk of ischaemic events in additional vascular beds, reflecting the generalized nature of atherosclerosis and atherothrombosis. PAD is a marker of atherosclerosis affecting the coronary and cerebrovascular arterial beds, and is a predictor of ischaemic stroke (IS), MI and overall mortality. In CAPRIE, patients who qualified on the basis of PAD were at high risk of further ischaemic events in additional vascular territories. The 3-year event rates for cerebrovascular outcomes (fatal or non-fatal IS) were 3.6% in the clopidogrel group versus 5.2% in the aspirin group. Those for coronary outcomes (fatal or non-fatal MI) were 4.2% and 5.1%, respectively. 1 1 Dormandy JA. Ankle:arm blood pressure index as a predictor of atherothrombotic events: evidence from CAPRIE. Cerebrovasc Dis 1999;9(Suppl 1):1 – 128 (Abstr 4).
- 5-year natural history of PAD PAD is often undiagnosed. For every 100 patients who present with intermittent claudication, there are approximately 100 more with symptoms who do not present to their physician, and another 100 with asymptomatic disease. Of the 100 patients presenting, only around 25% will have deterioration of their condition locally. In contrast, after 5 years, only approximately 50% will be alive without having had a cardiovascular event. Therefore, pharmacological therapy in PAD patients should aim to improve the symptoms and local prognosis, provide an adjuvant to interventional measures, and, most importantly, modify cardiovascular mortality and morbidity. 1 Dormandy JA. Natural history of intermittent claudication. Hosp Update 1991;April:314–318.
- PAD mortality – 10-year survival rates of subjects in the San Diego Artery Study The San Diego study referred to earlier also evaluated the mortality rate from all cardiovascular disease and coronary heart disease in a free-living population. Of 565 subjects examined (average age 66 years), 67 patients (11.9%) were identified as having large-vessel PAD by non-invasive testing. The patients were then followed prospectively for 10 years. Shown are Kaplan-Meier survival curves (based on mortality from all causes) for four groups of patients: normal, asymptomatic, symptomatic and severely symptomatic. The survival curves demonstrate a poor prognosis for patients with PAD; even asymptomatic patients had sharply reduced survival, compared with normal subjects. The subgroup with severe symptomatic PAD had the worst prognosis: analysis of this group revealed a 15-fold increase in rates of mortality due to cardiovascular disease and CHD. After 10 years, about half of asymptomatic patients had survived, whereas only 25% of severely symptomatic patients had survived. 1 1 Criqui MH, Langer RD, Froner A et al . Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381–386.
- Relative 5-year PAD mortality rates versus other common pathologies The overall survival rate for patients with PAD who have intermittent claudication is only 72% at 5 years and approximately 50% at 10 years. These survival rates are much lower than those for age-adjusted controls, for whom the rate is 90% at 5 years. Additional evidence suggests that atherosclerosis in other locations further increases a patient's mortality risk. 1 Five-year mortality rates in PAD patients are higher than rates obtained in another study in patients with breast cancer or those with Hodgkin’s disease. 2 The mortality rate of patients with PAD demonstrate that they should receive careful cardiovascular evaluation, and undergo counselling and treatment to manage risk factors such as smoking, hyperlipidaemia, hypertension, sedentary lifestyle, obesity and diabetes. 1 Kampozinski RF, Bernhard VM. Introduction and general considerations. In: Vascular Surgery (Rutherford RB, ed) Philadelphia, PA: WB Saunders: 1989;chap 53. 2 American Cancer Society. Cancer Facts and Figures – 1997.
- Intermittent claudication – an independent risk factor for increased mortality rates In the Whitehall study, 1 a 17-year follow-up study of 18 388 male civil servants aged 40 – 64 years, mortality rates for deaths due to coronary heart disease, cerebrovascular disease or all cardiovascular disease were higher in subjects with probable intermittent claudication; the mortality rate due to non-cardiovascular diseases was unaffected. Possible cases of intermittent claudication demonstrated increased mortality due to both cardiovascular and non-cardiovascular disease. Furthermore, possible and probable cases still showed increased cardiovascular and all-cause mortality even after adjustment for coronary risk factors (not shown), suggesting that the elevated mortality risk seen with PAD is independent of coexisting cardiovascular disease and risk factors. 1 Smith GD, Shipley MJ, Rose G. Intermittent claudication, heart disease risk factors, and mortality: the Whitehall study. Circulation 1990;82:1925 –1931.
- Low ABPI is a strong predictor of cardiovascular mortality PAD, as measured by ABPI (ankle:brachial pressure index), is a strong predictor of mortality. In a Belgian study of 2023 asymptomatic working men aged 40–55 years who were free of coronary artery disease, the predictive power of an ABPI of < 0.9 was evaluated. 1 The age-adjusted relative risks for reduced versus normal ABPI were 4.16 ( p = 0.011) and 4.97 ( p = 0.006) for 10-year cardiovascular and coronary mortality, respectively. A reduced ABPI was a significant independent predictor of cardiovascular and coronary mortality, with ORs of 3.29 ( p = 0.046) and 3.63 ( p = 0.046), respectively. These data confirm that a reduced ABPI is a strong risk factor for cardiac mortality, even in asymptomatic, middle-aged males. In a US, 10-year, global mortality study involving 744 patients, there was a powerful inverse relationship between the PAD severity as assessed by ABPI and mortality. 2 Causes of death were grouped into four categories: ischaemic heart disease, cardiovascular diseases other than ischaemic heart disease; cancer; and other causes. Analysis of 10-year survival for the four categories of mortality showed a definite trend towards increased risk of death from cardiovascular diseases, particularly ischaemic heart disease, with decreasing ABPI. 2 Also, 1.5–5% of patients with intermittent claudication develop critical leg ischaemia, necessitating amputation. 3 1 Kornitzer M, Dramaix M, Sobolski J et al . Ankle/arm pressure index in asymptomatic middle-aged males: an independent predictor of ten-year coronary heart disease mortality. Angiology 1995;46:211 – 219. 2 McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991;87:119–128. 3 Dormandy JA, Mahir M, Ascady G et al . Fate of the patients with chronic limb ischaemia. J Cardiovasc Surg 1989;30:50–57.
- ABPI – inverse relationship with 5-year risk of cardiovascular events and death The CAPRIE trial, discussed previously, represents the largest prospective study of patients with symptomatic PAD. Data on entry ankle:brachial pressure index (ABPI) were available for 2180 of the patients who qualified with PAD. Analysis showed that there was a significant 10.2% increase in relative risk for major vascular ischaemic events (ischaemic stroke [IS], MI, vascular death) for every 0.1 decrease in ABPI . 1 1 Dormandy JA, Creager MA. Ankle:arm blood pressure index as a predictor of atherothrombotic events: evidence from CAPRIE. Cerebrovasc Dis 1999; 9(Suppl 1):1 – 128 (Abstr 4).
- Symptomatology of PAD Intermittent claudication, the most common manifestation of PAD, consists of severe pain while walking and/or weakness of the calf muscles during exercise that is relieved by rest. A small percentage of patients with intermittent claudication (1.5–5%) 1 develop critical leg ischaemia, which causes pain at rest and may result in gangrene and amputation of the affected limb. According to the Fontaine classification, the common interpretation of the various stages involving severe ischaemia is as follows: stage 1, asymptomatic with no functional signs; stage 2, intermittent claudication; stage 3, rest pain caused by arterial disease; and stage 4, ulceration and/or gangrene caused by arterial disease. 2 1 Dormandy JA, Mahir M, Ascady G et al . Fate of the patient with chronic limb ischaemia. J Cardiovasc Surg 1989;30:50–57. 2 European Working Group on Critical Leg Ischemia. Second European Consensus Document on Chronic Critical Leg Ischemia. Circulation 1991;84(Suppl IV):IV1–IV26.
- Diagnosis of PAD Non-invasive testing has come to occupy an important position in the testing of patients for PAD. Physical examination can often provide information on the site of atherosclerotic involvement by obvious pulse deficits or by the presence of a bruit at sites of arterial stenosis. Measurement of the ankle:arm blood pressure index (ABPI) has been validated as a way of screening individuals with some of the risk factors for atherosclerotic diseases such as PAD. 1 The rationale behind this measurement is that the drop in blood pressure between thigh and toe is significantly larger than that observed in healthy subjects. The ABPI measurement is a powerful predictor of subsequent morbidity and mortality, and has the advantage of being simple, non-invasive and suitable for inclusion as part of a routine screen for cardiovascular risk. Exercise testing on a treadmill can provide additional objective measurements on the severity and progression of PAD. 1 Shinozaki T, Hasegawa T, Yano E. Ankle–Arm Index as an indicator of atherosclerosis: its application as a screening method. J Clin Epidemiol 1998;15:1263–1269.
- Management of PAD patients A key element of the management of PAD is risk-factor modification. In patients with PAD, morbidity and mortality can be significantly decreased by stopping smoking, taking regular exercise (three times a day), and reducing dietary fat intake. Importantly, pharmacological treatment should include secondary prevention of ischaemic events of atherothrombotic origin by an antiplatelet agent. Pharmacological treatment to reduce cholesterol, and to control diabetes and hypertension, where present, is also important. These risk-factor modification strategies also apply to reduction of ischaemic risk in patients with symptomatic atherosclerosis affecting the coronary and cerebral arterial beds. Cilostazol, a phosphodiesterase inhibitor, has recently been approved by the FDA for the reduction of symptoms, as measured by pain-free and maximal walking distance, for patients with intermittent claudication. 1,2 Pentoxifylline is an earlier therapy for intermittent claudication; however, a critical review of placebo-controlled trials has concluded that the improvement in walking distance obtained with pentoxifylline is often unpredictable and may not be clinically significant. 3 It is important to note that although symptomatic benefit may be obtained from vasodilator therapy, there is still a need to prescribe an antiplatelet agent that effectively reduces the risk of vascular ischaemic events such as ischaemic stroke, MI and vascular death. PAD also has considerable consequences upon patients’ community-based quality of life, and this can be significantly improved by exercise programmes. Additionally, a recent study highlighted the repercussions of PAD upon professional activities, with nearly half of patients stating that PAD had caused either a change in their activities, or partial suspension or cessation of work. 4 However, following treatment with naftidrofuryl, less than 10% of patients were on sick leave or required external assistance as a result of the disease (6-month follow-up), leading to improved quality of life (rather than positive outcomes). 1 Dawson DL, Cutler BS, Meissner MH et al . Cilostazol has beneficial effects in treatment of intermittent claudication. Results from a multicenter, randomized, prospective, double-blind trial. Circulation 1998;98:678–686. 2 Money SR, Herd JA, Isaacsohn JL et al . Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998;27:267–275. 3 Radack K, Wyderski RJ. Conservative management of intermittent claudication. Ann Intern Med 1990;113:135–146. 4 Rolland N, Lebrun T, Comte S et al . Conséquences de l'artériopathie oblitérante des membres inférieurs (AOMI) sur l'activité professionnelle des patients et sur les aides extérieures. J Mal Vasc 1999;24:208–139 (in French).
- Management of PAD – intervention Intervention, either by direct reconstruction of diseased leg arteries by angioplasty (with or without subsequent stent placement), endarterectomy or by replacement by peripheral bypass grafting, can relieve symptoms caused by inadequate blood flow. The decision to operate should be based on symptom severity, degree of disability and perceived surgical risk. When performed by an experienced surgeon, vascular surgical procedures are associated with a lower mortality rate than amputation. 1 Obviously, interventions affecting the peripheral arteries do not reduce ischaemic risk in the cerebral or coronary arteries thus, chronic antiplatelet therapy and risk factor modification are still needed. 1 Kampozinski RF, Bernhard VM. Introduction and general considerations. In: Vascular Surgery (Rutherford RB, ed) Philadelphia, PA: WB Saunders: 1989;chap 53.
- Management of PAD – antiplatelet agents are a key component of treatment The use of antiplatelet agents in secondary prevention stems from the central role of platelet aggregation in atherothrombosis. Ticlopidine is a platelet ADP receptor antagonist, inhibiting the ADP-dependent pathway of platelet activation. Data on antiplatelet agents in PAD patients reviewed in the APTC meta-analysis 1 is based largely on ticlopidine, approved in several countries for secondary prevention in PAD patients. Clopidogrel, a newer ADP receptor antagonist, is the first antiplatelet agent to be approved for the prevention of all major vascular ischaemic events (iscahemic stroke [IS], MI, vascular death) in all patients with atherothrombosis manifested by recent IS, recent MI or established PAD. 2 Aspirin inhibits the thromboxane A 2 pathway of platelet activation, but there are few clinical trial data on aspirin in PAD patients, therefore the drug has not been approved for secondary prevention in this setting. 1 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. 2 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
- CAPRIE – study design Clopidogrel was compared with aspirin in the CAPRIE trial, a randomized, blinded study in patients with a wide spectrum of atherosclerotic disease. 1 This approach was based on the belief that these patients are at risk of all major atherothrombotic events (ischaemic stroke [IS], MI, vascular death), and that the efficacy of antiplatelet agents has been shown to be consistent across the different clinical manifestations of atherothrombosis. Patients entered into the study had one of three qualifying conditions: (i) recent ischaemic stroke; (ii) recent MI; or (iii) PAD evidenced by current intermittent claudication or prior arterial intervention. Patients were followed for a minimum of 1 to a maximum of 3 years, regardless of discontinuation of study drug. The primary endpoint was a composite outcome cluster of IS, MI or vascular death. 1 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
- CAPRIE – efficacy profile of clopidogrel Clopidogrel was found to be more effective than aspirin, with an 8.7% relative risk reduction in the combined risk of ischaemic stroke (IS), MI or vascular death ( p = 0.043). 1 This is in addition to the 25% odds reduction for a similar outcome cluster (all-cause stroke, MI, vascular death) that is accepted to be provided by aspirin. 2 A favourable trend was noted for each component of the primary outcome cluster of IS, MI and vascular death, with the greatest relative risk reduction (19.2%) observed for MI ( p = 0.008). 3,4 Clopidogrel could be expected to prevent 24 outcome events for every 1000 patients treated for 1 year, compared with 19 events prevented using aspirin. This represents an increase of 26% in the number of events prevented per 1000 patients per year. When these results are extrapolated to the estimated 20 million patients with atherothrombosis in the USA and Western Europe, a staggering 100 000 new major vascular events could be prevented each year by using clopidogrel instead of aspirin. 1 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 2 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. 3 Easton JD. Benefit of clopidogrel in patients with symptomatic cerebrovascular disease. Neurology 1998;50(Suppl 4):A157. 4 Gent M. Clopidogrel, a new potent adenosine (ADP)-receptor antagonist for the prevention of myocardial and ischemic stroke. Today’s Therapeutic Trends 1998;16:237–254.
- Safety profile of clopidogrel In CAPRIE, the overall incidence of adverse events was similar for clopidogrel and aspirin. 1 Clopidogrel showed better overall gastrointestinal safety than aspirin with a reduced risk of gastrointestinal bleeding, including related hospitalizations 2 and gastrointestinal ulcers. 3 Since CAPRIE excluded patients with a known sensitivity to or intolerance of aspirin, an even greater gastrointestinal safety advantage can be expected in everyday clinical practice. The rate of neutropenia during clopidogrel therapy was very low, being comparable to that of aspirin. Clopidogrel’s high tolerability and low toxicity mean that neither dosing adjustments nor specific patient monitoring are necessary with clopidogrel therapy. 1 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 2 Bogousslavsky J. Lower gastrointestinal bleeding with clopidogrel compared with aspirin. Cerebrovasc Dis 1998;8(Suppl 4):43. 3 Lok DJA. Comparative gastrointestinal tolerability of clopidogrel and aspirin: results from the CAPRIE trial. Eur Heart J 1998;19(Abstract Suppl):52.
- Summary – 1 PAD is a manifestation of atherothrombosis – a global disease requiring global treatment. Epidemiological studies have shown that PAD is a marker of atherosclerosis in the coronary and cerebral arteries, and that PAD is a risk factor for ischaemic stroke, myocardial infarction and all-cause mortality. Bearing in mind the morbidity and mortality associated with PAD, it is clear that PAD is a condition that requires careful screening and diagnosis, management of risk factors (in particular smoking cessation and regular exercise training) and adequate treatment. Importantly, treatment goals should include secondary prevention of atherothrombotic events through the use of a proven antiplatelet agent. There is good evidence that the ankle:arm blood pressure index (ABPI) is a powerful predictor of ischaemic risk in patients with PAD, even with asymptomatic disease. The ABPI measurement has the advantage of being non-invasive, technically simple and easy to perform, and should be considered for inclusion in routine screening for cardiovascular risk.
- Summary – 2 Clopidogrel, an ADP receptor antagonist, provides increased benefit over aspirin for the secondary prevention of major vascular ischaemic events (ischaemic stroke, myocardial infarction, vascular death) in all atherothrombotic patients, including those with diagnosed PAD. Clopidogrel also offers a more favourable gastrointestinal safety and tolerability profile than aspirin.