ASCET: Single Antiplatelet Therapies Compared in Stable CAD

November 26, 2010

November 26, 2010 (Chicago, Illinois) — Patients with stable coronary artery disease (CAD) who require single antiplatelet therapy and who are nonresponsive to aspirin should probably switch to clopidogrel, says the lead author of a new study, Aspirin Nonresponsiveness and Clopidogrel Endpoint (ASCET), which was presented at the American Heart Association (AHA) 2010 Scientific Sessions last week. The discussant of the trial agrees that aspirin nonresponders should switch therapy, but argues that they would be better off on a more potent antiplatelet agent than clopidogrel.

ASCET author Dr Alf-Aage Pettersen (Oslo University Hospital, Norway) explained to heartwire that patients with stable CAD still have a high risk for thromboembolic events and can be on a single antiplatelet agent for many, many years, so the question of which drug is best for reducing risk in a specific patient "is very important."

Investigators say ASCET is the only other study, apart from the landmark CAPRIE trial, to examine the issue of single antiplatelet therapy and to compare aspirin with clopidogrel in patients at risk of ischemic events, he noted. ASCET examined whether patients with high platelet reactivity on aspirin (nonresponders) had worse clinical outcomes than aspirin responders, and also if aspirin nonresponders fared better by switching to clopidogrel.

"The answer to both questions was no, this was a negative trial," discussant Dr Jurriën M ten Berg (St Antonius Hospital, Nieuwegein, the Netherlands) told heartwire . However, says ten Berg, the absolute reduction in the primary composite endpoint seen in aspirin nonresponders who switched to clopidogrel compared with those who stayed on aspirin was "quite striking," he noted, adding that the trial was "really underpowered" to demonstrate a significant difference "but I guess the essence is real."

However, ten Berg says he doesn't think clopidogrel is a great choice of agent to switch to, because studies have shown that 50% of patients who are resistant to aspirin will also be resistant to clopidogrel. A stronger antiplatelet agent, such as the investigational agent, ticagrelor, would be a better choice, he noted, although he conceded that cost may be a limiting factor in choice of therapy in many instances. A more potent antiplatelet agent might be a particularly good option for secondary prevention in high-risk patients, such as those with diabetes, he noted.

Also, the ASCET researchers did not use the best platelet function test to assess aspirin nonresponsiveness, he said; they used the PFA100 method, which he says is "unreliable" for aspirin. "If I were to do this trial again I would use a greater number of patients, a different [platelet function] test, and I would not go for clopidogrel."

Negative Trial With Positive Messages

"We are focusing most of the time on PCI patients, but stable CAD patients, who are all mostly only on aspirin, have a mortality of about 20% in registries, which is high," ten Berg observes.

ASCET is the first prospective randomized trial to investigate the relation of platelet function tests to clinical outcomes in patients with symptomatic, stable CAD, on single antiplatelet therapy. 1001 patients with stable CAD on aspirin 160mg/day were randomized to continue treatment with the same dose of aspirin or to switch to clopidogrel 75mg/day. Platelet function was also assessed at randomization with the PFA100 method and platelet aggregometry. The patients were followed for up to two years, and the primary endpoint was a composite of all-cause death, nonfatal MI, ischemic stroke, and unstable angina.

There was no difference in the number of primary endpoint events between the randomized groups (56/503 on aspirin vs 50/498 on clopidogrel; p=0.57).

In all, 26% of patients had high on-treatment platelet reactivity at randomization and were deemed aspirin nonresponders, but this did not significantly influence occurrence of the primary endpoint (13.1% in nonresponders vs 10.5% in responders, p=0.41).

If I was a patient [on aspirin and] had high on-treatment platelet reactivity, I would like to switch to clopidogrel because it would reduce my risk of events.

But among aspirin nonresponders randomized to clopidogrel, there was a 40% reduction in the combined endpoint compared to aspirin responders randomized to continue aspirin (7.7% vs 13.1%, p=0.16). Pettersen acknowledged that this finding was not statistically significant, but agreed with ten Berg that the study was greatly underpowered.

"The study found that aspirin and clopidogrel are equally good," Pettersen said. "If I was a patient who was supposed to use aspirin, I personally would like to do a platelet function test and if I had high on-treatment platelet reactivity, I would like to switch to clopidogrel because it would reduce my risk of events," he told heartwire .

More Work Needed on Best Platelet Function Test for Aspirin

Pettersen agrees, however, that the question of which test to use is key. "The most important thing is to have a platelet function test and relate it to clinical endpoints." He points out that ASCET began in 2002, before a lot of the platelet function tests that are available now were in use.

"I am not sure that the PFA100 will be a gold-standard test in the future, as the field of platelet function testing is an evolving field with a lot of unsolved issues. But I don't think this test so far has proven to be unreliable to evaluate platelet reactivity as a risk factor for new clinical events," he commented. 

ten Berg says that although there is consensus on the best four platelet function tests to use to assess responsiveness to clopidogrel [1], there is as yet no agreement on the best test to use for aspirin.

Pettersen has no conflicts. ten Berg has received speakers fees from Sanofi-Aventis, Eli Lilly, BMS, and  MSD; and consults for Sanofi-Aventis, Eli Lilly, Schering-plough, and GlaxoSmithKline.



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