SAN FRANCISCO -- Drilling down into data from a head-to-head trial of ticagrelor (Brilinta) and clopidogrel (Plavix) revealed that the investigational agent did a better job of reducing strokes, heart attacks, and cardiovascular deaths in acute coronary syndrome patients who were destined for stenting before randomization.
The prespecified subset analysis of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial found that for every 1,000 patients admitted to the hospital with a planned invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths, 13 fewer MIs, and six fewer cases of stent thrombosis, said Christopher Cannon, MD, of Brigham and Women's Hospital in Boston.
Action Points
- Explain to interested patients that this report describes results of a study of an investigational drug that is not approved for clinical use.
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
At 12 months, 10.65% of the clopidogrel patients versus 9.02% of the ticagrelor patients met the primary endpoint of cardiovascular death, MI, or stroke -- a 16% relative risk reduction (P=0.0025).
Ticagrelor is a direct-acting inhibitor of the adenosine diphosphate receptor P2Y12.
Cannon reported results of the analysis, PLATO Invasive, today at a late-breaking clinical trials session at the Transcatheter Cardiovascular Therapeutics meeting here.
The study analyzed data from a subset of 13,408 patients who were identified by investigators as "intent for invasive strategy." The total PLATO population was 18,624 ACS patients.
In PLATO, 9.8% of patients randomized to ticagrelor reached the composite endpoint of cardiovascular death, stroke, or myocardial infarction compared with 11.7% of those randomized to clopidogrel. Those numbers also worked out to a relative reduction of 16% (P<0.001).
Cannon said the new analysis is particularly useful because "this is the way we treat patients. They come into the emergency department and they are identified as needing invasive treatment."
Among the "therapeutic considerations" Cannon cited were these: "treating 59 patients with ticagrelor instead of clopidogrel for one year would prevent one cardiovascular death, MI, or stroke. Treating just 88 patients would save one life in one year."
Asked how he would use these data to inform his decision about which antiplatelet to use -- clopidogrel, prasugrel, or ticagrelor -- Cannon said it was unlikely that there would ever be one antiplatelet to fit all ACS patients.
But he said two factors were likely to tip the scale in favor of ticagrelor -- a mortality benefit and the fact that the drug turns on and off quickly, the same two factors that were repeatedly cited when the full PLATO data were reported at the European Society of Cardiology meeting three weeks ago.
Cannon said cardiologists have been looking for an antiplatelet that can be quickly turned off, and with ticagrelor the antiplatelet activity is "pretty much gone 48 hours after stopping the drug."
Ron Waksman, MD, of the Washington Hospital Center in Washington, DC, said he was not convinced that the mortality benefit was as impressive as it has been presented.
He noted, for example, "there does not appear to be a mortality benefit in the first 30 days and that is when the risk is highest."
Ajay Kirtane, MD, SM, of Columbia University in New York City, also cautioned about overinterpreting mortality findings "from a trial that was not powered for mortality."
Waksman and Kirtane were discussants at the late-breaking plenary session where the findings were reported.
The multicenter, double-blind study PLATO trial randomized 18,624 ACS patients to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 to 600 mg loading dose, 75 mg thereafter). Patients were followed for 12 months.
There was no increase in major bleeding with ticagrelor and no need for transfusions.
The one side effect that might be troublesome was dyspnea. Cannon said that for every 1,000 patients treated with ticagrelor rather than clopidogrel, six were likely to switch to clopidogrel because of reversible breathing problems.
This side-effect has led Waksman and others to suggest that patients known to have breathing difficulties are not good candidates for the drug.
Disclosures
The PLATO trial was funded by AstraZeneca.
Cannon disclosed research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems.
Kirtane said he was a consultant to Medtronic CardioVascular, Abbott Vascular, Boston Scientific, St. Jude Medical, and the Medicines Company.
Waksman said he had no financial disclosures.
Primary Source
Transcatheter Cardiovascular Therapeutics
Source Reference: Cannon, CP et al "PLATO -- Invasive Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATelet Inhibition and patient Outcomes trial" TCT 2009; Late-breaking clinical trials II.