A major meta-analysis tips the balance in a long-running antiplatelet debate, while a leading Aussie expert weighs in.
Aspirin’s long reign as the default antiplatelet for secondary prevention in coronary artery disease (CAD) may be ending, with new evidence showing clopidogrel offers superior protection against heart attack, stroke and cardiovascular death – without increasing bleeding risk.
A patient-level meta-analysis published in The Lancet pooled data from seven randomised trials including nearly 29,000 patients on monotherapy after stopping or never starting dual antiplatelet therapy.
Over 5.5 years of follow-up, clopidogrel was associated with a 14% lower risk of major cardiovascular and cerebrovascular events compared with aspirin (HR 0.86, 95% CI 0.77–0.96), with no difference in major bleeding.
The international authors said recommendations for lifelong aspirin were based on outdated evidence predating modern pharmacotherapies and revascularisation strategies.
They described clopidogrel as the only antiplatelet consistently more effective than aspirin without compromising safety and highlighted its affordability and generic availability as reasons for broad adoption.
“This comprehensive synthesis of available evidence indicates that, in patients with CAD, long-term clopidogrel monotherapy offers superior protection against major cardiovascular and cerebrovascular events compared with aspirin, without an excess risk of bleeding,” they wrote.
“The superior efficacy of clopidogrel versus aspirin was consistent across multiple key subgroups, including individuals with clinical features predictive of poor clopidogrel responsiveness, supporting the generalisability of these findings to the broad spectrum of patients with CAD.
“These results support a preference for clopidogrel over aspirin for chronic antiplatelet monotherapy for patients with stable CAD. The widespread availability, generic formulation, and affordability of clopidogrel further supports its potential for extensive adoption in clinical practice.”
Cardiologist and director and CEO of the Victor Chang Cardiac Research Institute Professor Jason Kovacic told The Medical Republic that the Lancet paper was “really good”.
“It’s been done by really good scientists, and I have no reservations or questions about the findings,” he said.
“There’s always the usual limitations with meta-analysis, but this is an individual patient level meta-analysis, rather than an aggregate summary level meta-analysis. So that’s great.
“I think the findings are consistent with a whole lot of other data and studies and clinical practice and so on, which is all pointing towards the fact that we may be getting to the end of an era of us using aspirin for cardiovascular risk protection, and that maybe there are better agents like clopidogrel or others that in the near future will replace aspirin as the preferred agent
“This paper was in the context of cardiovascular disease risk protection. The other population that really commonly is on aspirin monotherapy is patients that have had a coronary stent.
“Initially, after a coronary stent, you go into aspirin plus clopidogrel. But the tried and tested path is that after a year you would drop the clopidogrel and then remain on aspirin monotherapy indefinitely once you’ve had a stent, so 12 months after a stent. And there are also data in on those patients with some broadly similar findings.”
One thing mentioned in the paper but not in great detail was the effect of the CYP2C19 loss-of-function genetic alleles on clopidogrel’s efficacy.
“Basically, what it all boils down to is a certain percent of people [who carry the gene] and it’s a fairly low percentage, but it’s still not insignificant, don’t respond to clopidogrel.
“So when you put them on clopidogrel you don’t get much effect, and these patients are at risk of thrombosis and clot.
“There wasn’t a lot of data in the studies that were combined into the meta-analysis regarding the status of the CYP2C19 alleles in those subjects, so really this meta-analysis couldn’t address the question of what about those people where the clopidogrel is not going to work.”
Professor Kovacic told TMR that this presented a clinical challenge which would need to be overcome before abandoning aspirin as the frontline treatment.
There is also another drug in the mix which has potential to step in, he said. Ticagrelor is another antiplatelet drug showing positive results. Professor Kovacic said it was used “somewhat interchangeably with clopidogrel”.
He said a study known as the Twilight Study, led by Dr Roxana Moran (who was also an author on the recent Lancet paper) showed that ticagrelor monotherapy, after a period of aspirin and then dropping that aspirin, was better.
“So ticagrelor doesn’t have this issue about the CYP2C19, so ticagrelor may ultimately be the drug we settle on.
“But the problem with ticagrelor is it’s probably slightly stronger even than clopidogrel, and for most people it’s probably a little too strong.”
In Australia it’s only available at a 90mg taken twice a day. There is a 60mg version that is not yet available here but is in the US.
“I think that’s probably a good way to sum up the whole field [to say] we haven’t quite landed it yet,” he told TMR.
“But there is very much a wave of sentiment that this may be the final period of having aspirin as our go-to, which it has been for decades.
“I think we’re coming to the end of that period. We’re just not quite there yet in terms of which way to jump.
“Do we just use clopidogrel in everybody and forget about the genetic testing and that genetic issue?
“Do we start doing genetic testing or point of care testing for the effectiveness of clopidogrel? That’s another option.
“Do we go for a lower dose of ticagrelor that hasn’t really been widely tested yet?
“These are the sort of options on the table, and I think it will be the focus of a lot of attention in the coming years, because I think it’s clear we can do better than aspirin.
“We just don’t know exactly how to do that in the clinic for individual patients.”
