Time to switch patients from aspirin to clopidogrel for secondary prevention?

Hossain is 68, and he has been taking aspirin since he had a myocardial infarction successfully stented three years ago. He has come to see you about his peripheral neuropathy but at the end of the consultation he pulls out his smart phone and scrolls to a newspaper story heralding an alternative drug is ‘better than aspirin’ at preventing stroke and heart attacks. ‘Should I be taking that Doctor?’ ask Hossain.. ‘Um, which drug is this….?’ you ask. 

Of course, you may well have already come across the story Hossain is showing you, given the widespread media attention it received. The story refers to a recent meta-analysis comparing the safety and efficacy of clopidogrel to aspirin monotherapy for secondary prevention of coronary artery disease, which was published in the Lancet. 

Data were pooled from seven original randomised trials including almost 29,000 patients. The primary outcome was a composite of cardiovascular death, stroke or myocardial infarct (MACCE) with major bleeding the primary safety outcome. Patients randomised to clopidogrel had a 14% lower relative risk of this primary outcome (hazard ratio 0.86, 95%CI: 0.77 to 0.96) with a similar risk of major bleeding and overall mortality between the two groups. This is important because other anti-thrombotic interventions have tended to increase the risk of bleeding compared to aspirin, even if they have offered superior prevention against major cardiovascular events. The authors conclude that their “findings support the consideration of clopidogrel as the preferred long-term antiplatelet strategy instead of aspirin in patients with established coronary artery disease”. 

So, is it time to start gearing up a for a large Quality Improvement Project and switch all our patients on long-term aspirin over to clopidogrel? Perhaps not just yet. Although the hazard ratio was in favour of clopidogrel, the absolute differences between the treatments were small; the incidence rate of the primary MACCE outcome among patients assigned to aspirin was 2·99 per 100 patient-years across the studies, compared to 2.61 per 100 patient-years in those assigned to clopidogrel. Whilst both drugs are cheap, aspirin remains cheaper and available as an over-the-counter medication. It will be interesting to see what NICE recommend once cost-effectiveness has been taken into account. As with many trials, males were over-represented and the median age was 65 years with relatively few older participants. Although the primary outcome was reported at 5.5 years, follow-up was much shorter for many patients and the median follow-up was only 2.3 years. The longer-term merits of clopidogrel in comparison to aspirin across a breadth of populations therefore remains less certain than the headline results of this study suggest. 

Another potential issue to consider is clopidogrel resistance. As we know, clopidogrel is a pro-drug and genetic variants can impair the conversion to the active metabolite. These variants are more common in Asian populations. Interestingly, two thirds of the participants in the meta-analysis were from Asia and reassuringly the results were consistent across ethnic groups. Although only one of the original studies included in the meta-analysis had actually undertaken clopidogrel genotype testing, the results of this were consistent with the main findings. Furthermore, there is an ABCD clinical score to predict resistance, but a sub-group analysis in the review based on this score again showed similar results. Does this mean clopidogrel resistance a myth? No, but interestingly recent research suggests the decreased efficacy of clopidogrel in those with genetic variance may be most important in the relatively small proportion of people with a homozygous gene mutation. Furthermore, any decreased efficacy has largely been reported in studies where clopidogrel is used for acute treatment and there is less certainty about its importance with long-term use. 

So, in conclusion what does this mean for Hossain and others like him? The 2024 ESC Guidelines already supports clopidogrel as an alternative to aspirin for long-term secondary prevention of coronary disease, and this latest research supports that recommendation. However, the absolute treatment benefit appears too small to warrant a widespread switch from aspirin to clopidogrel at this stage. That said, it’s a discussion worth having on a case-by-case basis and for patients who wish to make the change both the evidence and the ESC guidelines would support that decision.

And if you feel like a deeper dive into all things related to primary care cardiology, including ECG interpretation and discussion of the latest research, do join us for our next live and interactive Cardiology & ECG course on Friday 7th November or on demand at a time that suits you.