Efficacy and Costs of Secondary Prevention with Antiplatelets after Ischaemic Stroke
BACKGROUND AND PURPOSE
Ischaemic stroke and other atherothrombotic events substantially increase the medico-economic burden because of their high treatment costs and longlasting disabilities with need for chronic care. Studies have shown that the cost of stroke represents 3-5% of annual health budget. Antiplatelet agents play a major role in secondary stroke prevention. Acetylsalicylic acid (ASA), ASA combined with extended-release dipyridamole (ER-DP), and clopidogrel are all acceptable choices for first-line treatment in the secondary prevention of stroke. The newer antiplatelets, however, are more expensive than ASA, and their cost-effectiveness is not easily estimated.
The table summarises some published data about direct and indirect stroke costs from several countries.
Country-specific Costs of Poststroke Treatment per Patient
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| Country |
Year |
Author |
Time frame |
Costs |
Currency |
Euro* |
| Australia |
2001 |
Dewey |
1 year |
18,956 |
Aus$ |
11,168 |
| Australia |
2001 |
Dewey |
Lifetime |
44,428 |
Aus$ |
26,176 |
| Netherlands |
1995 |
Bergman |
Lifetime |
81,000 |
DGL |
33,215 |
| France |
2004 |
Launois |
5 years |
34,638 |
Euro |
34,638 |
| UK |
2003 |
Youman |
5 years |
29,405 |
GBP |
42,166 |
| Sweden |
2004 |
Ghatnekar |
Lifetime |
638,910 |
SKE |
70,274 |
| USA |
1994 |
Taylor |
Lifetime |
90,981 |
US$ |
70,392 |
| *Costs in Euro based on 2004 exchange rates. |
ACETYLSALICYLIC ACID (ASA)
ASA is still the most extensively investigated antiplatelet drug. ASA irreversibly inhibits prostaglandin H synthase (cyclooxygenase-1) in platelets and megakaryocytes, and thereby blocks the formation of thromboxane A2 (TXA2; a potent vasoconstrictor and platelet aggregant). Because platelets are unable to regenerate cyclooxygenase, the immediate antithrombotic effect of ASA remains for the lifespan of the platelets (8-10 days). As normal haemostasis may be regained when 20% of platelets have normal cyclooxygenase activity, daily ASA intake is recommended.
Sites of Action of Antiplatelet Drugs
EFFICACY OF DIFFERENT ANTIPLATELET DRUGS
ASA has to be given to 33 stroke patients to prevent one future stroke, myocardial infarction (MI) or vascular death compared with placebo. Adding ER-Dip to ASA increases the benefit for the patients. A total of 33 stroke patients had to be treated with this combination, instead of ASA, to prevent one stroke. However, the combination of ASA plus ER-Dip does not prevent MI, vascular death or the combined end point of either stroke or death. Clopidogrel is more effective than ASA in preventing a combined end point of ischaemic stroke, MI, or vascular death, but it has not been shown to be superior to ASA in preventing recurrent stroke in transient ischaemic attack or stroke patients. Several subgroups, such as stroke patients with additional peripheral artery disease, patients with prior coronary artery bypass, patients with insulin-dependent diabetes, and patients with recurrent vascular events, were identified, in whom the benefit of clopidogrel is amplified.
Efficacy of Different Antiplatelet Drugs in Preventing Further Vascular Events
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| Drug |
Compared with |
Populatoin |
End point |
Period (years) |
RRR (%) |
ARR (%) |
NNT |
| ASA |
Placebo |
Stroke and TIA |
IS, MI
and VD |
2 |
13.0 |
3.0 |
33 |
| ASA + ER-Dip |
Placebo |
Stroke and TIA |
Stroke |
2 |
37.0 |
5.8 |
18 |
| ASA + ER-Dip |
ASA |
Stroke and TIA |
Stroke |
2 |
23.1 |
3.0 |
33 |
| Clopidogrel |
ASA |
Symptomatic atherosclerotic vascular disease - CAPRIE patients |
IS, MI
and VD |
3 |
8.7 |
0.5 |
200 |
| Clopidogrel |
ASA |
CAPRIE patients
with stroke
and PAD |
IS, MI
and VD |
3 |
16.1 |
3.9 |
26 |
| Clopidogrel |
ASA |
CAPRIE patients
with previous
cardiac surgery |
IS, MI
and VD |
1 |
36.3 |
3.3 |
33 |
| Clopidogrel |
ASA |
CAPRIE patients
with insulin-
dependent diabetes mellitus |
IS, MI
and VD,
rehospita-
lisation |
3 |
17.7 |
3.8 |
26 |
| Clopidogrel |
ASA |
CAPRIE patients
with recurrent
vascular events |
IS, MI
and VD |
1 |
14.9 |
1.4 |
71 |
| Ticlopidine |
Placebo |
Stroke |
IS, MI
and VD |
1 |
30.2 |
14.5 |
23 |
| Ticlopidine |
ASA |
Stroke and TIA |
IS, MI
and VD |
3 |
12 |
2 |
50 |
| ARR: Absolute risk reduction; ASA: Acetylsalicylic acid; CAPRIE: Clopidogrel versus ASA in Patients at Risk of Ischaemic Events; ER-Dip: Extended release dipirydamole; IS: Ischaemic stroke; MI: Myocardial infarction; PAD: Peripheral artery disease; RRR: Relative risk reduction; TIA: Transient ischaemic attack; VD: Vascular death. |
Results of the CAPRIE Study: Treatment Effect on Outcome by Subgroup
In patients treated with clopidogrel, the event rate (vascular death, MI, IS) per year was 14.9% lower (ARR: 1.4%) compared with the patients treated with ASA. This risk reduction translates into a NNT of 71 patients per year with clopidogrel instead of ASA to prevent one further vascular event, compared with 200 patients per year for the overall study cohort.
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| Subgroup |
Number of events/patient-years at risk |
RRR (95% CI) |
ARR |
| |
Clopidogrel |
ASA |
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| Ischaemic stroke |
433/6054 |
461/5979 |
7.3 (-5.7 - 18.7) |
0.56 |
| Myocardinal infarction |
291/5787 |
283/5843 |
-3.7 (-22.1 - 12.0) |
-0.19 |
| Peripheral artery disease |
215/5795 |
277/5797 |
23.8 (8.9 - 36.2) |
1.15 |
| All patients |
939/17636 |
1021/17519 |
8.7 (0.3 - 16.5) |
0.51 |
| ARR: Absolute risk reduction; ASA: Acetylsalicylic acid; RRR: Relative risk reduction. |
Bleeding rates of different antiplatelet drugs.
The data from the ESPS 2 trial in the table illustrate that dipyridamole does not add to the bleeding risk associated with ASA.
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| Agent |
Any bleeding |
Severe bleeding |
| ASA low dose |
8.2% * / 9.2% � |
1.2% *# / 0.5% �** |
| ASA + ER-Dip |
8.7% * |
1.6% *# |
| Clopidogrel |
9.3% � |
0.4% �** |
| Ticlopidine |
Missing data |
0.3% �# |
* Data from ESPS-2. � Data from CAPRIE. � Data from CATS.
# Severe or fatal bleeding. ** Intracranial bleeding.
ASA: Acetylsalicylic acid; ER-Dip: Extended release dipyridamole. |
CONCLUSION
Taking economical aspects into account, the fixed combination of ASA and ER-Dip can be recommended for secondary stroke prevention as a first-line alternative to ASA in patients without major comorbidity. In patients with higher comorbidity, clopidogrel may be more effective for the individual patient compared with ASA, and might also be cost-effective. Furthermore, in patients with ASA intolerance clopidogrel is a useful, but expensive, alternative.
PubMed Abstract
Reference:
Ringleb et al. Expert Opin Pharmacother 2005; 6 (3): 359-367.
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