CHICAGO – A triple-antiplatelet regimen that added cilostazol to the standard combination of clopidogrel and aspirin proved noninferior to a double-dose clopidogrel plus aspirin regimen during 30 days following placement of drug-eluting coronary stents in a randomized trial with 3,755 patients conducted in South Korea.
Results from the HOST-ASSURE (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Safety and Effectiveness of Drug-Eluting Stents and Anti-Platelet Regimen) trial showed that both the triple, cilostazol-containing regimen and the double-dose clopidogrel regimen were "slightly stronger than conventional-dose clopidogrel, effective, and safe," Dr. Hyo-Soo Kim said at the meeting.
During the first 30 days following placement of either everolimus- or zotarolimus-eluting coronary stents, daily, oral treatment with 100 mg aspirin, 75 mg clopidogrel, and 100 mg cilostazol taken twice daily led to a 1.2% cardiovascular event rate, compared with a 1.4% rate among patients who received 100 mg aspirin plus 150 mg clopidogrel once daily, reported Dr. Kim, director of coronary catheterization at Seoul (South Korea) National University Hospital.
Although these results come from the largest, controlled test of cilostazol as part of an antiplatelet regimen following the placement of drug-eluting coronary stents, the generalizability and definitiveness of the findings came under question for three reasons, experts said.
Mitchel L. Zoler/IMNG Medical Media
Dr. Hyo-Soo Kim
First, by being studied in Korea, a population known to have a high prevalence of genetic unresponsiveness to clopidogrel, the results probably do not directly apply to other populations with higher levels of clopidogrel responsiveness. Second, the unexpectedly low rate of adverse coronary events during the 30 days of treatment that was roughly half the expected rate made the study underpowered by about half in its ability to clearly prove a noninferior relationship between the two treatments. And third, in the United States, initial treatment of patients following drug-eluting stent use in percutaneous coronary intervention (PCI) increasingly involves the newer drugs prasugrel (Effient) or ticagrelor (Brilinta), a development that makes comparison of cilostazol to double-dose clopidogrel (Plavix) less relevant.
The study is "a very hard to interpret, underpowered noninferiority trial," commented Dr. E. Magnus Ohman, an interventional cardiologist and professor of medicine at Duke University in Durham, N.C.
"Cilostazol is extensively used [in Korea and elsewhere in East Asia], but has not really been tested, so for Korea this is an important trial. If you do a noninferiority trial, it needs to be sized to be sure of the effect you see, but their result is very comforting because their point estimate is on the right side," Dr. Ohman noted, with the cilostazol-containing regimen leading to fewer events than the comparator regimen.
Dr. Magnus Ohman
"Cilostazol has not caught on in the United States," in part because "before this study, there was not a lot of evidence on cilostazol, so this study solves that problem, but it is hard to predict how this study might translate into U.S. practice," Dr. Ohman said in an interview.
"Cilostazol is a relatively weak anti-platelet agent, and more and more people are becoming aware that clopidogrel, although it has been terrific, also has limitations," he noted.
As a result of problems with clopidogrel’s potency and reliable efficacy in all patients, many U.S. physicians increasingly prescribe prasugrel plus aspirin or ticagrelor plus aspirin for the first weeks following PCI, said Dr. Ohman and other cardiologists. "There has been slow adoption" of prasugrel and ticagrelor into U.S. practice, but more recently U.S. physicians "have become more comfortable with the trade-off" of reduced coronary events with either prasugrel or ticagrelor despite the small increase in bleeding complications both drugs cause, he said.
"Prasugrel and ticagrelor have become the standard of care [for U.S. practice following PCI] for patients who are not at excessive risk for bleeding," commented Dr. Gregg W. Stone, an interventional cardiologist and professor of medicine at Columbia University in New York.
Dr. George Dangas
The HOST-ASSURE results "are very applicable for Korea and East Asian populations, and is not generalizable to the United States," commented Dr. George D. Dangas, professor of medicine and director of cardiovascular innovation at Mount Sinai Medical Center in New York. In the United States, "prasugrel and ticagrelor are steadily becoming more used, mostly in the first month [following PCI] in higher-risk patients. The trend is to go with prasugrel or ticagrelor rather than try different dosages of clopidogrel," he said in an interview.
The HOST-ASSURE trial enrolled patients with an average age of about 63 years; about two-thirds were men. The primary efficacy endpoint after 1 month of treatment was a composite of cardiac death, nonfatal myocardial infarction, stroke, definite or probable stent thrombosis, and major bleeding events. The 1,879 patients randomized to the cilostazol arm received a 200-mg loading dose of cilostazol when they started their regimen. The 1,876 patients randomized to the double-dose clopidogrel arm received no loading dose of the drug.