This study has a complicated design which makes it tricky to interpret. Essentially, it supports previous evidence that any difference in the effectiveness of these two regimens in preventing further events in people who have had a stroke is likely to be extremely small at a population level.
Prescribers should continue to follow NICE guidance and offer low dose aspirin plus extended-release dipyridamole as first choice antiplatelet regimen for most people with a history of stroke or TIA (transient ischaemic attack).
What is the background to this?
There is good evidence that antiplatelet drugs reduce the risk of recurrent stroke and other vascular events in people who have suffered a stroke or TIA. But which regimen should prescribers choose? Two earlier studies, ESPS2 and ESPRIT, had shown the superiority of aspirin plus extended release dipyridamole over aspirin alone in secondary prevention of stroke. In CAPRIE, clopidogrel was marginally more effective than aspirin alone in secondary prevention of vascular events in patients with a variety of primary events, but was no different from aspirin in the patients with previous ischaemic stroke (although the study was not powered for subgroup analysis). Finally, the MATCH study found that aspirin plus clopidogrel was no more effective than clopidogrel alone in secondary prevention of vascular events in stroke patients, but caused more life-threatening bleeds.
What went on in this study?
In this analysis of the PRoFESS trial, investigators compared aspirin 25 mg plus extended release dipyridamole 200 mg, both twice daily (ASA-ERDP); with clopidogrel 75 mg once a day in 20,332 patients who had had a recent ischaemic stroke, for a mean of 2.5 years. (The other analysis of PRoFESS, which looked at the possible benefits of telmisartan in stroke prevention, has been blogged separately). ProFESS was sponsored by the manufacturers of telmisartan and dipyridamole.
What did this study find?
There was no statistically significant difference in the primary outcome, the rate of recurrent stroke: this occurred in 9.0% of the patients receiving ASA-ERDP and 8.8% of those receiving clopidogrel (Hazard ratio [HR] 1.01, 95% confidence intervals [95%CI] 0.92 to 1.11). There was also no difference in the secondary outcome, the composite of stroke, myocardial infarction or death from vascular causes (HR 0.99, 95%CI 0.92 to 1.07). Although there were more major haemorrhagic events in the ASA-ERDP group than the clopidogrel group (HR 1.15, 95% CI, 1.00 to 1.32, NNH=200), a post-hoc analysis found that the net risk of stroke, myocardial infarction, death from vascular causes or major haemorrhage (“all bad vascular things happening”) was the same in both groups (HR 1.00, 95%CI 0.93 to 1.07).
This trial does not substantially change what we already thought about antiplatelet regimens in people with a history of stroke or TIA. Reviewing the direct and indirect evidence available from all the large trials in this area, including this one, the authors of the accompanying editorial rank ASA-ERDP minimally (and not significantly) ahead of clopidogrel, which itself would rank slightly (and not significantly) ahead of aspirin.
The statistical design of this trial was slightly different to many trials, and this makes its interpretation complicated. It was designed to test first if ASA-ERDP was not inferior to clopidogrel, and then test to see if it was superior. According to the very demanding pre-defined criterion for non-inferiority, the study cannot rule out the possibility that ASA-ERDP is inferior to clopidogrel. However, as the authors make clear, this does not mean that clopidogrel has been shown to be superior to ASA-ERDP. Any difference between the two regimens is likely to be extremely small at a population level.
All in all then, NICE guidance from 2005 still seems appropriate for most patients. This recommends ASA-ERDP as first choice regimen for most people with a history of stroke or TIA for 2 years from the most recent event. Thereafter, or if extended -release dipyridamole is not tolerated, preventative therapy should revert to standard care, including long-term treatment with low-dose aspirin. Clopidogrel monotherapy is recommended as an alternative in people intolerant of aspirin (i.e. with proven aspirin hypersensitivity or a history of severe dyspepsia caused by low dose aspirin). This study adds nothing about the optimum duration of ASA-ERDP treatment.
It would be a step too far to argue from this study that clopidogrel should be used instead of aspirin monotherapy for secondary prevention of stroke (as having a similar efficacy to ASA-ERDP). There is no good, direct evidence that clopidogrel is superior to aspirin alone in this indication: the best we can say is that it is not superior to ASA-ERDP.
Finally, as there is no robust evidence for a significant benefit in terms of effectiveness or safety, one must also consider cost: Aspirin monotherapy costs a few pence a month. ASA-ERDP costs around £9 a month (depending on aspirin category M price changes) whereas clopidogrel costs more than four times this. In purely financial terms, stroke is extremely expensive for the NHS to manage but this study does not seem to warrant a re-examination of NICE’s cost-effectiveness analysis.
As the authors of the accompanying editorial conclude:
“In the case of PRoFESS and the tangle of related trials, enlightenment might be expressed simply, as a haiku:
For stroke prevention,
use an antiplatelet drug.
Patients: 20,332 patients who had had a recent ischaemic stroke.
Intervention: aspirin 25 mg plus extended release dipyridamole 200 mg, both twice daily.
Comparison: clopidogrel 75 mg once a day.
Outcome: Primary outcome (recurrent stroke):9.0% of the patients receiving ASA-ERDP and 8.8% of those receiving clopidogrel (Hazard ratio [HR] 1.01, 95% confidence intervals [95%CI] 0.92 to 1.11). Secondary outcome: (composite of stroke, myocardial infarction or death from vascular causes) HR 0.99, 95%CI 0.92 to 1.07.
More information about management of stroke and TIA can be found on the relevant section of NPC