Asprin Dosage in US May Explain Disparity in Ticagrelor Results in PLATO 1

Although the PLATO trial succeeded in demonstrating the overall superiority of ticagrelor (Brilinta, AstraZeneca) to clopidogrel in more than 18,000 ACS patients worldwide, approval of the drug in the US has been delayed because of ticagrelor’s lack of effect in the prespecified subgroup of patients from North America. Now, two  analyses of the trial, presented at the American Heart Association’s Emerging Science Series (a new peer-reviewed venue from the AHA), suggest that the North American results may be the result of more use of high dose aspirin in patients from the US. The paper has now also been published online in Circulation.

Ken Mahaffey presented the results from the analyses, which were performed by the Duke Clinical Research Institute and AstraZeneca. The analyses were not able to rule out the play of chance as an explanation for the North American subgroup, but did show that high dose aspirin >300 mg/day was used far more often in the US than in the rest of the world (53.6% vs 1.7%).

Mahaffey reported that in patients taking low-dose aspirin, the outcomes were better in the ticagrelor group than in the clopidogrel group. The difference was statistically significant in the rest of the world but not in the US:

  • For  high dose aspirin in the US, the hazard ratio for ticagrelor patients was 1.62 (CI 0.99-2.64).
  • For patients taking low dose (<100 mg/day) aspirin in the US, the HR for ticagrelor was 0.73 (CI 0.40-1.33).
  • For patients taking high dose aspirin  outside the US, the hazard ratio for ticagrelor patients was 1.23 (CI 0.71-2.14).
  • For patients taking low dose (<100 mg/day) aspirin outside the US, the HR for ticagrelor was 0.78 (CI 0.69-0.87).

In an AHA press release, Mahaffey said that “physicians choosing to use ticagrelor in countries where it is approved and available should consider using a low-dose of maintenance aspirin with the drug.”

Here is the AHA press release:

New study suggests potent antiplatelet drug effective with low-dose aspirin

Study Highlights:

  • When taken with higher doses of aspirin (more than 300 milligrams), the experimental antiplatelet drug ticagrelor was associated with worse outcomes than the standard drug, clopidogrel, but the opposite was true with lower doses of aspirin.
  • The study is a secondary analysis of a clinical trial that compared the two drugs and found ticagrelor to be less effective in North America than in other countries.
  • Researchers suggest the aspirin dose in combination with anti-clotting medicine may alter ticagrelor’s effectiveness.

DALLAS, June 27, 2011 – The experimental antiplatelet drug ticagrelor prevented significantly more cardiovascular complications than the standard medication clopidogrel when used with low-dose aspirin, according to new research reported in the American Heart Association’s Emerging Science Series webinar.

However, patients taking ticagrelor with high-dose aspirin fared worse than those taking clopidogrel, according to the researchers’ new analysis of data from a clinical trial comparing the drugs. Both drugs are used to prevent potentially dangerous blood clots from forming in patients with acute coronary syndromes, including those who have suffered a heart attack.

The new analysis found that patients taking ticagrelor with less than 300 milligrams of aspirin daily were 16 percent less likely than those taking clopidogrel with low-dose aspirin to have a heart attack, stroke or to die within a year.

In the initial analysis of the data from the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor was less effective than clopidogrel in North America but not in other parts of the world. Researchers examined the PLATO data to determine why these regional differences occurred. While they could not exclude chance, they identified aspirin dose as a potential explanation.

Ticagrelor is already approved for use in some countries but still under Federal Drug Administration review in the United States.

“Patients with acute coronary syndrome have options to prevent recurrent events,” said Kenneth W. Mahaffey, M.D., lead author and co-director of cardiovascular research at the Duke Clinical Research Institute, and associate professor of medicine at Duke University Medical Center. “Physicians choosing to use ticagrelor in countries where it is approved and available should consider using a low-dose of maintenance aspirin with the drug.”

Co-authors are Daniel M. Wojdyla, M.S.; Kevin Carroll, M.S.; Richard C. Becker, M.D.; Robert F. Storey, M.D., D.M.; Dominick J. Angiolillo, M.D., Ph.D.; Claes Held, M.D., Ph.D.; Christopher P. Cannon, M.D.; Stefan James, M.D., Ph.D.; Karen S. Pieper, M.S.; Jay Horrow, M.D.; Robert A. Harrington, M.D.; and Lars Wallentin, M.D., Ph.D.

Author disclosures are on the abstract. AstraZeneca funded the study.

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  1. Pingback: AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval « CardioBrief

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