Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/11/14 For personal use only.
Drug Profile
Front-loading with clopidogrel plus aspirin followed by dual antiplatelet therapy in the prevention of early stroke recurrence Expert Rev. Neurother. Early online, 1–12 (2014)
Bruno Censori Stroke Unit, A.O. Papa Giovanni XXIII, Piazza OMS, 1, 24128 Bergamo, Italy Tel.: +39 035 267 3330 Fax: +39 035 267 4853 [email protected]
Dual antiplatelet therapy with aspirin plus clopidogrel is not recommended for secondary stroke prevention because of lack of effectiveness and increased hemorrhagic risk. Recent studies show that in patients with a very recent transient ischemic attack or minor ischemic stroke loading with 300 mg clopidogrel plus aspirin, followed by clopidogrel 75 mg plus aspirin once daily for up to 90 days significantly decreases the rate of recurrent stroke, especially strokes that occur within few days from the event that led to medical attention, without an increase in severe bleedings. This article reviews the pharmacokinetics and pharmacodynamics of clopidogrel, focusing on loading doses, and summarizes the results of the studies that have shown the effectiveness of the front-loading approach in the early secondary prevention of stroke. KEYWORDS: clopidogrel • dual antiplatelet therapy • front-loading • secondary prevention • stroke
Randomized clinical trials have shown that clopidogrel 75 mg q.d. is slightly superior to aspirin 325 mg/day for secondary stroke prevention [1] and as effective as the combination of extended-release (ER) dipyridamole 200 mg b.i.d. plus aspirin 25 mg b.i.d. [2]. On the contrary, the combination of clopidogrel 75 mg and aspirin has shown no clear superiority over aspirin alone for stroke prevention in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance trial [3], and in patients with a lacunar stroke in the Secondary Prevention of Small Subcortical Strokes trial [4], although the combination appeared superior to aspirin when given to patients with a history of cardiovascular or cerebrovascular symptoms in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance study (TABLE 1) [5]. Furthermore, clopidogrel 75 mg plus aspirin 75 mg/day were not superior to clopidogrel alone for secondary stroke prevention in the Management of Atherothrombosis with Clopidogrel in High-Risk informahealthcare.com
10.1586/14737175.2014.923758
Patients trial (TABLE 1) [6]. Only in patients with nonvalvular atrial fibrillation unfit for anticoagulant treatment, clopidogrel 75 mg plus aspirin 75–100 mg q.d. have resulted in a significant 11% reduction in major vascular events and a significant 26% reduction in stroke incidence compared with aspirin alone (TABLE 1) [7]. However, this was a setting of primary prevention. Thus, the 2008 European Stroke Organization Guidelines for the Management of Ischemic Stroke and Transient Ischaemic Attack stated that ‘compared with clopidogrel alone, the combination of aspirin and clopidogrel did not reduce the risk of ischaemic stroke, MI, vascular death, or re-hospitalization; however, life-threatening or major bleeding was increased with the combination’, and the 2011 Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack of the American Heart Association concluded that ‘The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not recommended for routine secondary prevention... (Class III;
2014 Informa UK Ltd
ISSN 1473-7175
1
doi: 10.1586/14737175.2014.923758
Ischemic stroke or TIA
MI, PAD, Stroke/TIA, diabetes + risk factors
Stroke or TIA
Lacunar stroke
MATCH
CHARISMA
CHARISMA Stroke/TIA
SPS3
3020
325
75–162
75–162
15,603
4320
75
ASA (mg)
7599
Number
Median 62 days
30.8% £1 mo
18 mos
19% £7 days 42% £1 mo mean 26.5
3.4 years
25 mos
28 mos
F-up
From index symptom
All data are percentages. ASA: Aspirin; Clop.: Clopidogrel; mo: Month; MI: Myocardial infarction; PAD: Peripheral arterial disease.
Setting
Study
Table 1. Previous studies with clopidogrel + aspirin. p
ns
ns
ns
0.03
6.1
Stroke
9.6
0.09
0.09
Primary outcome
2.4
Nonfatal stroke
7.3
Primary outcome
9.1
Stroke
16.7
2.5
3.1
2.7
Stroke x year
3.4
ns
ns
Major vascular events x year
4.9
8.1
1.9
6.8
8.9
15.7
Clop. or ASA
Primary outcome
ASA + Clop.
Primary outcome/stroke p
ns
Drug Profile
Front-loading with clopidogrel plus aspirin followed by dual antiplatelet therapy in the prevention of early stroke recurrence Expert Rev. Neurother. Early online, 1–12 (2014)
Bruno Censori Stroke Unit, A.O. Papa Giovanni XXIII, Piazza OMS, 1, 24128 Bergamo, Italy Tel.: +39 035 267 3330 Fax: +39 035 267 4853 [email protected]
Dual antiplatelet therapy with aspirin plus clopidogrel is not recommended for secondary stroke prevention because of lack of effectiveness and increased hemorrhagic risk. Recent studies show that in patients with a very recent transient ischemic attack or minor ischemic stroke loading with 300 mg clopidogrel plus aspirin, followed by clopidogrel 75 mg plus aspirin once daily for up to 90 days significantly decreases the rate of recurrent stroke, especially strokes that occur within few days from the event that led to medical attention, without an increase in severe bleedings. This article reviews the pharmacokinetics and pharmacodynamics of clopidogrel, focusing on loading doses, and summarizes the results of the studies that have shown the effectiveness of the front-loading approach in the early secondary prevention of stroke. KEYWORDS: clopidogrel • dual antiplatelet therapy • front-loading • secondary prevention • stroke
Randomized clinical trials have shown that clopidogrel 75 mg q.d. is slightly superior to aspirin 325 mg/day for secondary stroke prevention [1] and as effective as the combination of extended-release (ER) dipyridamole 200 mg b.i.d. plus aspirin 25 mg b.i.d. [2]. On the contrary, the combination of clopidogrel 75 mg and aspirin has shown no clear superiority over aspirin alone for stroke prevention in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance trial [3], and in patients with a lacunar stroke in the Secondary Prevention of Small Subcortical Strokes trial [4], although the combination appeared superior to aspirin when given to patients with a history of cardiovascular or cerebrovascular symptoms in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance study (TABLE 1) [5]. Furthermore, clopidogrel 75 mg plus aspirin 75 mg/day were not superior to clopidogrel alone for secondary stroke prevention in the Management of Atherothrombosis with Clopidogrel in High-Risk informahealthcare.com
10.1586/14737175.2014.923758
Patients trial (TABLE 1) [6]. Only in patients with nonvalvular atrial fibrillation unfit for anticoagulant treatment, clopidogrel 75 mg plus aspirin 75–100 mg q.d. have resulted in a significant 11% reduction in major vascular events and a significant 26% reduction in stroke incidence compared with aspirin alone (TABLE 1) [7]. However, this was a setting of primary prevention. Thus, the 2008 European Stroke Organization Guidelines for the Management of Ischemic Stroke and Transient Ischaemic Attack stated that ‘compared with clopidogrel alone, the combination of aspirin and clopidogrel did not reduce the risk of ischaemic stroke, MI, vascular death, or re-hospitalization; however, life-threatening or major bleeding was increased with the combination’, and the 2011 Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack of the American Heart Association concluded that ‘The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not recommended for routine secondary prevention... (Class III;
2014 Informa UK Ltd
ISSN 1473-7175
1
doi: 10.1586/14737175.2014.923758
Ischemic stroke or TIA
MI, PAD, Stroke/TIA, diabetes + risk factors
Stroke or TIA
Lacunar stroke
MATCH
CHARISMA
CHARISMA Stroke/TIA
SPS3
3020
325
75–162
75–162
15,603
4320
75
ASA (mg)
7599
Number
Median 62 days
30.8% £1 mo
18 mos
19% £7 days 42% £1 mo mean 26.5
3.4 years
25 mos
28 mos
F-up
From index symptom
All data are percentages. ASA: Aspirin; Clop.: Clopidogrel; mo: Month; MI: Myocardial infarction; PAD: Peripheral arterial disease.
Setting
Study
Table 1. Previous studies with clopidogrel + aspirin. p
ns
ns
ns
0.03
6.1
Stroke
9.6
0.09
0.09
Primary outcome
2.4
Nonfatal stroke
7.3
Primary outcome
9.1
Stroke
16.7
2.5
3.1
2.7
Stroke x year
3.4
ns
ns
Major vascular events x year
4.9
8.1
1.9
6.8
8.9
15.7
Clop. or ASA
Primary outcome
ASA + Clop.
Primary outcome/stroke p
ns
