Use Low-Dose Aspirin With Ticagrelor: PLATO

June 28, 2011

June 27, 2011 (Updated 28, 2011) (Dallas, Texas) — The antiplatelet ticagrelor (Brilinta, AstraZeneca) seems to work better at preventing clinical events in patients with ACS when it's accompanied by low-dose as opposed to high-dose aspirin, suggests a new analysis of the PLATO trial that is being interpreted cautiously by both its investigators and expert observers [1]. Low-dose aspirin was defined as <300 mg/day, high-dose aspirin as doses above that threshold.

Such an interaction between aspirin dosage and ticagrelor effects could possibly explain the trial's so-called "North American anomaly," in which outcomes were superior with the new drug vs clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) across the entire international trial but not in North America, where the aspirin doses were generally higher, as previously covered by heartwire .

Those divergent outcomes are thought to be the reason why US regulators have postponed decisions on whether to approve ticagrelor, while the drug has already been approved for the PLATO indication in Canada, Europe, and other parts of the world. An FDA decision on ticagrelor is expected by July 20, also as reported by heartwire .

PLATO enrolled >18 000 patients in 43 countries on nearly every continent. In it, as heartwire has covered extensively, ticagrelor was associated with a 16% reduction in the composite primary end point vs clopidogrel, with both drugs accompanied by aspirin, over a mean of 12 months. In the overall trial, the absolute rates were 9.8% for those taking ticagrelor and 11.7% for the clopidogrel group (p<0.001).

But in a prospectively defined subgroup analysis, as previously reported, the rates were 11.9% and 9.6%, respectively, for US and Canada patients; the difference didn't reach significance. The new PLATO analysis by geography, presented by Dr Kenneth W Mahaffey (Duke University, Durham, NC) in an internet-only presentation billed as part of an Emerging Science series sponsored by the American Heart Association (AHA), broke the geographic regions down further by comparing the 1413 patients randomized in the US with 17 211 randomized in other countries. The analysis was also published in Circulation to coincide with the online presentation.

In a panel discussion that followed Mahaffey's live presentation, some observers questioned the strength of the findings, with one calling them "spurious," in large part because they come from an underpowered post hoc subgroup analysis. Mahaffey himself said the findings could have been the result of chance.

But some on the panel also proposed that the results fit into a picture that seems to have developed in recent years, suggesting that the aspirin dosage used in the US may not be as appropriate overall as the lower dosages used elsewhere.

The Geography-Aspirin Analysis From PLATO

As reported by Mahaffey, geographic variation in the relative ticagrelor-vs-clopidogrel effect on outcomes was evident for the composite primary end point, for some of its components, and for all-cause mortality, but not for major bleeding.

Clinical Outcomes in PLATO for US vs Non-US, Ticagrelor vs Clopidogrel

End point US (n=1413), hazard ratio (95% CI), p Non-US (n=17 211), hazard ratio (95% CI), p
CV death/MI/stroke 1.27 (0.92–1.75), 0.1459 0.81 (0.74–0.90), <0.0001
CV death 1.26 (0.69–2.31), 0.4468 0.77 (0.67–0.89), 0.0005
MI 1.38 (0.95–2.01), 0.0956 0.80 (0.70–0.90), 0.0004
Stroke 1.75 (0.51–5.97), 0.3730 1.15 (0.88–1.50), 0.2964
All-cause mortality 1.17 (0.68–2.01), 0.5812 0.77 (0.67–0.88), 0.0001
Major bleeding (PLATO criteria) 1.05 (0.76–1.45), 0.7572 1.04 (0.94–1.14), 0.4696

As Mahaffey reported, 53.6% of US patients vs 1.7% of patients elsewhere took a median aspirin dose of >300 mg/day for maintenance therapy; the rates of such high-dose aspirin were 69% and 37%, respectively, on the first day after randomization but fell to 55% and 2.4%, respectively, by day 30 and lower after 60 days.

In the trial overall, the ticagrelor-to-clopidogrel hazard ratio (HR) for the primary end point was 0.79 (95% CI, 0.71–0.88) for those getting low-dose aspirin and 1.45 (95% CI, 1.01–2.09) for those getting high-dose aspirin.

High-dose aspirin wasn't associated with a significant effect on the primary end point in either the US patients or those in the trial outside the US.

Primary Efficacy Outcome (CV Death, MI, or Stroke) by Geography, US vs Non-US, in PLATO

Aspirin dosage US, HR (95% CI) Non-US (95% CI)
>300 mg 1.62 (0.99-2.64) 1.23 (0.71–2.14)
>100 to <300 mg * 1.00 (0.71–1.42)
<100 mg 0.73 (0.40-1.33) 0.78 (0.69–0.87)

*Too few events to calculate

In analyses that accounted for 37 patient factors and characteristics at baseline and afterward (including other demographics, body-mass index and waist circumference, smoking status, troponin levels, other medications currently and before randomization, comorbidities, time to first aspirin dose at randomization, and history of revascularization), only differences in aspirin use explained a significant portion of the effect of geography on outcomes.

The main message of the geographic analysis, according to Mahaffey, is that when aspirin is given with ticagrelor for long-term maintenance therapy in patients with ACS, lower dosages "should be considered."

"Play of Chance as a Reasonable Explanation . . . "

Mahaffey said the geography-based aspirin findings were confirmed in separate analyses conducted independently by both AstraZeneca and the Duke Clinical Research Institute. But he was cautious to note that the observed variation in aspirin effect on the primary end point by country seen in PLATO could have arisen by chance. "I think many of the analyses we performed support the play of chance as a reasonable explanation for these findings," he said in a panel discussion that followed his presentation.

Also, he noted, there could have been unconsidered characteristics besides aspirin dosage that distinguished the US and non-US cohorts in the study and that could have caused variation in outcomes.

You get a p value that is really, really on the edges of statistical significance.

On that point, observed several members of the panel, US patients in PLATO had more CV risk factors and comorbidities and had undergone more invasive procedures than patients elsewhere in the world--the analysis of 37 patient factors and features notwithstanding.

US patients were heavier (mean 87 kg vs 80 kg in non-US countries); had more hypertension (71% vs 65%) and diabetes (33% vs 24%); had a greater history of prior MI (27% vs 20%), PCI (29% vs 12%), and CABG (17% vs 5%); and were more likely to have non-ST-segment-elevation ACS (persistent ST elevation, 15% vs 39%).

As the lone epidemiologist on the panel, Dr Donna Arnett (University of Alabama, Birmingham) was tapped to comment on the statistical strength of the geographic analysis. The US accounted for only 7.6% of patients in the trial, she noted, and although the "North American" cohort was prespecified, the US cohort was not. Plus, she said, "You get a p value that is really, really on the edges of statistical significance." So regarding the observed aspirin effect on regional variation in outcomes, she said, "I would probably take the argument that this is just a spurious finding."

Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA), a comoderator for the discussion, said that "when dealing with subgroup analyses, we've all learned to approach them with healthy dose of skepticism, especially when dealing with a subgroup defined by a postrandomization factor such as, in this case, the dose of aspirin." A substantial play of chance may have influenced the "region-by-treatment" interaction reported by PLATO investigators, he agreed.

Requiem for High-Dose Aspirin in ACS?

Regarding the optimal aspirin dosage in ACS, Antman added during the panel discussion, "If we look at the totality of evidence, we don't really have a lot of good evidence that high-dose aspirin is clearly better. And we also have a suggestion that it may be associated with a higher risk of gastrointestinal bleeding. So I think a clinical message for us here is that it's probably wise for us to start using low-dose aspirin," to make the transition from high- to low-dose during the maintenance phase "soon after we treat our patients with acute coronary syndrome, especially if they have had PCI."

Some very prominent interventionalists insisted that there be high-dose aspirin used in stenting, and I think it just got perpetuated into the guidelines.

Panelist Dr Eric R Bates (University of Michigan, Ann Arbor, MI) agreed, saying he "likes" the view that lower-dose aspirin should be preferred for patients with ACS. With the associated increased risks of bleeding, given the totality of evidence, "I see no strong rationale for using a high-dose aspirin, and this is another point that might support using lower-dose aspirin across the spectrum of acute coronary syndromes and stenting."

Bates also asked comoderator Dr Timothy J Gardner (Christiana Care Health System, Newark, DE), long involved in the development of guidelines for antiplatelet therapy and coronary revascularization appropriate-use criteria, how it happened that high-dose aspirin predominates in the US but not in other countries.

"I can't tell you why for sure," he said, but stent thrombosis was a major concern in the years when coronary stenting was becoming common. There was a "major push" to use high-dose aspirin with coronary stents, as was done in the early major stent trials, and it continued into clinical practice.

"So some very prominent interventionalists insisted that there be high-dose aspirin used in stenting, and I think it just got perpetuated into the guidelines," Gardner said.

Not "the Analysis They Need to Do"

In an interview, Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who recently published a critique of the PLATO data analysis [2], agreed that the data do suggest an interaction between geography and aspirin effect. "Which is what the FDA had suggested in the secondary review, showing a pattern in which a higher aspirin dose given with ticagrelor was associated with less benefit. That may probably be true."

But any variation by region or aspirin dose, he said, doesn't explain the inconsistencies he observed in the data reporting. He pointed to an FDA analysis that suggests that the reported PLATO outcomes numbers do not add up, in a way that makes the ticagrelor outcomes look better.

"The analysis that they need to do, and unfortunately it wasn't presented, is to compare the trial's outcomes in countries monitored by AstraZeneca vs those places monitored by independent clinical research organizations--the US, Russia, Georgia, and part of Ukraine," Serebruany said. "My biggest concern here is that since AstraZeneca monitored most sites, there may be some errors in data reporting."

Serebruany added, "The AHA should not be supporting this sort of activity three weeks before the FDA decision. For the person who does not have time to look at the webinar, it looks like an indirect endorsement of ticagrelor by the AHA. There is no new scientific value in what they presented from PLATO, it is not cutting-edge original research. The AHA should be very specific and selective about what it presents in this format if it cares about integrity and its reputation."

Mahaffey reports receiving research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado, Sanofi-Aventis, Schering-Plough, and the Medicines Company; and being a consultant or on an advisory board for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill, Sanofi-Aventis, and Schering-Plough. Antman discloses receiving research grants to the TIMI Study Group to investigate ticagrelor in the PEGASUS trial and to evaluate prasugrel in the TRITON-TIMI 38 study. Bates discloses consulting or serving on an advisory board for Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, Eli Lilly, Merck, AstraZeneca, GlaxoSmithKline, and Ikaria. Gardner and Arnett had no disclosures. As previously reported by heartwire , Serebruany is listed as an inventor for the US patent application "Treating cardiac arrhythmias, heart failure, peripheral artery disease and stroke with cyclopentyl-triazolopyrimidine or derivative thereof" (USN 61/253,829) assigned to HeartDrug Research. He received funding for research studies with clopidogrel and consultant fees from both clopidogrel and ticagrelor manufacturers. He is also the owner of HeartDrug Research.


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