Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.
OBJECTIVE
To examine the clinical effectiveness and cost-effectiveness of two alternative antiplatelet agents, clopidogrel and modified-release (MR)-dipyridamole, relative to prophylactic doses of aspirin for the secondary prevention of occlusive vascular events.


METHODS
Electronic databases.


METHODS
A total of 2906 titles and abstracts were rigorously screened and 441 studies were assessed in detail. Two RCTs were identified. For the assessment of cost-effectiveness, eight reviews were identified. The results were presented in structured tables and as a narrative summary. No additional clinical effectiveness data were presented in either of two company submissions. All economic evaluations (including accompanying models) included in the company submissions were assessed. Following this analysis, if the existing models (company or published) were not sufficient, a de novo model or modified versions of the models were developed.


RESULTS
In the CAPRIE trial the point estimate for the primary outcome, i.e. ischaemic stroke, myocardial infarction (MI) or vascular death, favoured clopidogrel over aspirin, but the boundaries of the confidence intervals raise the possibility that clopidogrel is not more beneficial than aspirin. In terms of the secondary outcomes reported, there was a non-significant trend in favour of clopidogrel over aspirin but the boundaries of the confidence intervals on the relative risks all crossed unity. There was no difference in the number of patients ever reporting any bleeding disorder in the clopidogrel group compared with the aspirin group. The incidences of rash and diarrhoea were statistically significantly higher in the clopidogrel group than the aspirin group. Patients in the aspirin group had a higher incidence of indigestion/nausea/vomiting than patients in the clopidogrel group. Haematological adverse events were rare in both the clopidogrel and aspirin groups. No cases of thrombotic thrombocytopenic purpura were reported in either group. Treatment with MR-dipyridamole alone did not significantly reduce the risk of any of the primary outcomes reported in ESPS-2 compared with treatment with aspirin. ASA-MR-dipyridamole was significantly more effective than aspirin alone in patients with stroke or transient ischaemic attacks (TIAs) at reducing the outcome of stroke and marginally more effective at reducing stroke and/or death. Treatment with ASA-MR-dipyridamole did not statistically significantly reduce the risk of death compared to treatment with aspirin. The number of strokes was statistically significantly reduced in the ASA-MR-dipyridamole group compared with the MR-dipyridamole group. In terms of the other primary outcomes, stroke and/or death and death, the results favoured treatment with ASA-MR-dipyridamole but the findings were not statistically significant. There was no difference in the number of bleeding complications between the ASA-MR-dipyridamole and aspirin groups. The incidence of bleeding complications was significantly lower in the MR-dipyridamole treatment group. More patients in the MR-dipyridamole treatment groups experienced headaches compared to patients receiving treatment with aspirin alone. The York model assessed the cost-effectiveness of differing combinations of treatment strategies in four patient subgroups, under a number of different scenarios. The results of the model were sensitive to the assumptions made in the alternative scenarios, in particular the impact of therapy on non-vascular deaths.


CONCLUSIONS
Clopidogrel was marginally more effective than aspirin at reducing the risk of ischaemic stroke, MI or vascular death in patients with atherosclerotic vascular disease, however, it did not statistically significantly reduce the risk of vascular death or death from any cause compared with aspirin. There was no statistically significant difference in the number of bleeding complications experienced in the clopidogrel and aspirin groups. MR-dipyridamole in combination with aspirin was superior to aspirin alone at reducing the risk of stroke and marginally more effective at reducing the risk of stroke and/or death. Compared with treatment with MR-dipyridamole alone, MR-dipyridamole in combination with aspirin significantly reduced the risk of stroke. Treatment with MR-dipyridamole in combination with aspirin did not statistically significantly reduce the risk of death compared with aspirin. Compared with treatment with MR-dipyridamole alone, bleeding complications were statistically significantly higher in patients treated with aspirin and MR-dipyridamole in combination with aspirin. Due to the assumptions that have to be made, no conclusions could be drawn about the relative effectiveness of MR-dipyridamole, alone or in combination with aspirin, and clopidogrel from the adjusted indirect comparison. The following would apply for a cost of up to GBP20,000-40,000 per additional quality-adjusted life-year. For the stroke and TIA subgroups, ASA-MR-dipyridamole would be the most cost-effective therapy given a 2-year treatment duration as long as all patients were not left disabled by their initial (qualifying) stroke. For a lifetime treatment duration, ASA-MR-dipyridamole would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered and all patients were not left disabled by their initial stroke. In patients left disabled by their initial stroke, aspirin is the most cost-effective therapy. Clopidogrel and MR-dipyridamole alone would not be considered cost-effective under any scenario. For the MI and peripheral arterial disease subgroups, clopidogrel would be considered cost-effective for a treatment duration of 2 years. For a lifetime treatment duration, clopidogrel would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered. It is suggested that the combination of clopidogrel and aspirin should be evaluated for the secondary prevention of occlusive vascular events. Also randomised, direct comparisons of clopidogrel and MR-dipyridamole in combination with aspirin are required to inform the treatment of patients with a history of stroke and TIA, plus trials that compare treatment with clopidogrel and MR-dipyridamole for the secondary prevention of vascular events in patients who demonstrate a genuine intolerance to aspirin.
Centre for Reviews and Dissemination, University of York, UK.
L
L
Jones
S
S
Griffin
S
S
Palmer
C
C
Main
V
V
Orton
M
M
Sculpher
C
C
Sudlow
R
R
Henderson
N
N
Hawkins
R
R
Riemsma
D001241:Aspirin / Q000191:economics / Q000627:therapeutic use; D000077144:Clopidogrel; D003362:Cost-Benefit Analysis; D003692:Delayed-Action Preparations; D003967:Diarrhea / Q000139:chemically induced; D004176:Dipyridamole / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use; D016527:Drug Costs / Q000706:statistics & numerical data; D003875:Drug Eruptions / Q000209:etiology; D004415:Dyspepsia / Q000139:chemically induced; D019317:Evidence-Based Medicine; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007511:Ischemia / Q000191:economics / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D017059:Models, Econometric; D009325:Nausea / Q000139:chemically induced; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use; D012107:Research Design / Q000592:standards; D012307:Risk Factors; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000191:economics / Q000627:therapeutic use; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000191:economics / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D014839:Vomiting / Q000139:chemically induced
D003692:Delayed-Action Preparations; D010975:Platelet Aggregation Inhibitors; D004176:Dipyridamole; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin