AHA: Ticagrelor bests Plavix in STEMI patients, includes mortality reduction
Orlando, Fla.—STEMI patients who received both aspirin and the new reversible oral antiplatelet drug ticagrelor (Brilinta; AstraZeneca) had few cardiac events and less mortality than patients on aspirin and the popular irreversible antiplatelet medication clopidogrel (Plavix; Bristol-Myers Squibb), based on the results of the PLATO STEMI trial, presented during Sunday’s late-breaking clinical trial session at the American Heart Association conference.

In the PLATO (PLATelet inhibition and patient Outcomes) trial, there was a subset of 8,430 patients who were in the midst of ST-elevation heart attacks (STEMI). Participants for randomized, double-blind trial were recruited from 862 sites in 43 countries between 2006 and 2008.

The 4,201 patients randomized to the investigative arm received 180 mg of ticagrelor during PCI, followed by 90 mg twice daily for six to 12 months. The other 4,229 patients received 300 mg of clopidogrel with a provision for an additional 300 mg during PCI, followed by 75 mg daily for six to 12 months. All patients in the trial in the trial also received daily aspirin therapy.

Patients with STEMI and unplanned primary PCI particularly require urgent and effective blockade of the P2Y12 platelet receptor, and also are potentially at greater risk of side effects from new therapies, according to lead investigator Philips Gabriel Steg, MD, director of the coronary care unit at Hopital Bichat, Claude Bernard Universite in Paris, who presented the study on behalf of the PLATO study group.

He said that the ticagrelor group suffered fewer cardiovascular events from the onset of the trial, and the benefits continued the longer patients took the drug during the year follow up.

Following the patients up to one year, the researchers found that 9.3 percent of the ticagrelor group met the primary endpoint—a composite of incidence of heart attack, stroke or vascular death—compared with 11 percent in the clopidogrel arm, which equates to a 15 percent relative risk reduction for the investigational group.

“The results are consistent with the overall trial results of the larger PLATO trial, namely the reduction in the primary endpoint with no increase in bleeding complications compared to clopidogrel,” Steg said.

He explained that since ticagrelor is a more potent agent than clopidogrel, which is currently recommended by the ACC/AHA guidelines, “bleeding was a concern.”

“The good news is that there was no sign of increased major bleeding regardless of how we defined it,” Steg noted.

“Clopidogrel’s drawbacks include a slower onset of effectiveness, which is not suited to the need for rapid effect in STEMI, and modest and inconsistent antiplatelet effect—many patients respond well, but a sizeable unresponsive group remains at high risk of blood clots despite therapy,” Steg said. He also noted that clopidogrel binds permanently to the platelets’ P2Y12 receptors, so its effects last seven to 10 days after the medication is stopped.

“With ticagrelor, there is a disassociation between the drug and the P2Y12 receptor so that the drug does not bind permanently to the receptor, and the receptor and the platelet can regain function, with normal platelet clotting ability returning in about four days,” according to Steg, who speculated that this leads to its lower bleeding incidence.

However, he also reported that ticagrelor has “off-target effects,” which “probably explains” the higher incidence of dyspnea—affecting 12.9 percent of ticagrelor patients and 8.3 percent of the clopidogrel group.

Overall mortality was reduced with ticagrelor—from 6 percent to 4.9 percent, with a relative risk of 18 percent. Stent thrombosis also was reduced from 1.6 percent in the ticagrelor arm versus 2.5 percent in the clopidogrel arm for definite stent thrombosis. Steg stressed that these mortality reduction rates are "new and important."

Steg concluded that the benefit of this new investigative agent “is not solely achieved during the first 30-days, or the acute phase, but the benefit accrues over time, so that the longer you treat, the greater the difference in event rates.”

In her commentary of the PLATO STEMI trial, Lisa K. Jennings, PhD, from the University of Tennessee Health Science Center in Memphis, Tenn., reviewed “potential explanations” with the positive findings for ticagrelor. She said the drug does not require metabolic activation unlike clopidogrel and prasugrel; causes stronger platelet inhibition with less variability than the thienopyridines; has a faster onset of action; and is reversible, which “may be an advantage in reducing bleeding.”

Jennings said that the potent P2Y12 blockade may be superior in relieving microvascular obstructions; preventing platelet accumulation, particularly in early stages of the thrombotic process; and reducing the massive aggregation of platelets in spaces between pre-existing thrombi.

“A more rapid reversible characteristic may make this agent well suited for inhibiting platelet function under appropriate clinical conditions while reducing the risk of bleeding complications,” she said.

However, Jennings concluded that reversible receptor binding and a 12-hour half-life necessitate twice-daily dosing, which “might be a challenge in patients who are not fully compliant.”

The London-based AstraZeneca funded the study.