ACC: Triple-antiplatelet therapy is non-inferior to double-dose of dual antiplatelets
CHICAGO—A popular three-pronged drug approach in Asia that adds chilostazol to dual antiplatelet therapy had comparable outcomes to a double-dose dual antiplatelet (DDAT) regimen, according to the results of the late-breaking HOST-ASSURE clinical trial presented March 25 at the 61st annual American College of Cardiology (ACC) scientific session.
Cilostazol is used in Western countries, but is not marketed frequently outside of Asia, and has not been evaluated in large-scale clinical trials.
The first month after PCI is a critical time due to the fact there are very high rates of thrombosis, said Hyo-Soo Kim, MD, PhD, the study’s principal investigator and director of cardiac catheterization and coronary intervention at Seoul National University Hospital, Republic of Korea, during a press conference. “Therefore we need stronger antiplatelet regimen the first month after PCI.”
There are two options for this, Kim said. A DDAT regimen, (150 mg clopidogrel and aspirin) is commonly used in high-risk PCI patients; however, in Asia, commonly cilostazol is added to dual-antiplatelet therapy (aspirin + 75 mg of clopidogrel)—what Kim et al deemed in the trial as triple antiplatelet therapy (TAT).
Because no previous trials have compared these two regimens, Kim et al conducted the HOST-ASSURE trial,a large randomized trial that used a 2 x 2 factorial design and enrolled 3,750 allcomers who received PCI.
The study also looked at the outcomes of two drug-eluting stents— platinum chromium everolimus-eluting stent (Promus Element) and the coating and a cobalt–chromium zotarolimus-eluting stent (Endevor Resolute). Kim said the results will be presented at next year’s meeting.
Cilostazol has been previously shown to prevent restenosis, vasodilation, improve lipid levels and protect the kidneys, Kim said.
During the HOST-ASSURE trial, 1,879 patients were randomized to receive TAT and 1,876 patients were randomized to receive DDAT. The entire patient cohort received between a 300 mg and 600 mg dose of clopidogrel plus a 300 mg dose of aspirin prior to PCI with TAT or without DDAT a loading dose of 20 mg of cilostazol. Those patients randomized to the TAT group also received a twice daily 100 mg dose of cilotazol for one-month post-procedure. Patients in the DDAT arm received a maintenance regimen of 150 mg of clopidogrel in addition to aspirin.
Kim et al used clinical outcomes (cardiac death, nonfatal MI, stroke and major bleeding) at one month as the study’s primary end point. Forty hospitals throughout Korea participated.
The study used a non-inferiority design, and is the largest clinical trial ever to be performed in South Korea, Kim noted.The primary end point occurred in 1.4 percent of patients in the DDAT group vs. 1.2 percent of those in the TAT arm.
Of the total cohort, one-third of patients were diabetic, one-third were smokers, one-third had stable angina and the average age was 62. Aspirin and clopidogrel was prescribed in more than 99 percent of patients at discharge.
“The non-inferiority of the trial was met,” Kim said. In fact, PLATO major bleeding rates were “exactly the same in both groups,” at 0.4 percent, which suggested safety, said Kim. Patients administered DDAT saw a slightly higher periprocedural MI event rate compared with those administered TAT, 0.69 percent vs. 0.37 percent, respectively. At one month, definite or probable stent thrombosis rates were also lower in patients administered TAT when compared with those administered DDAT, 0.21 percent vs. 0.37 percent, respectively.
In a per-protocol analysis, five MIs occurred in the 1,637 patients administered DDAT compared with zero MIs occurring in the 1,773 patients administered TAT.
Kim et al also performed a subgroup analysis based on age, sex, ACS, diabetes, renal dysfunction, and other factors, as part of the study evaluation. “There is no subgroup … that favors TAT or DDAT,” said Kim. “The results of the subanalysis are consistent with the results of all patients.”
Kim did report several study limitations:
Kim concluded that adding cilostazol to DAPT was non-inferior to the double-dosing strategy of clopidogrel, according to the clinical outcomes reported at one month. “Both regimens are slightly stronger than the conventional dose.”
“There were no differences between the two treatment regimens regarding the individual components of the primary outcome,” he summed.
Some panelists questioned whether this strategy would be generalizable to a wider population, as this study focused on the Asian population. Additionally, they also questioned why Kim et al chose a non-inferiority trial design, as it is more challenging to interpret. In response, Kim said, “We tried to establish a more feasible … four-week regimen in this trial.
“TAT is more important than DDAT in platelet inhibition and for that reason I think there is sufficient rational to introduce TAT into practice,” Kim summed.
Cilostazol is used in Western countries, but is not marketed frequently outside of Asia, and has not been evaluated in large-scale clinical trials.
The first month after PCI is a critical time due to the fact there are very high rates of thrombosis, said Hyo-Soo Kim, MD, PhD, the study’s principal investigator and director of cardiac catheterization and coronary intervention at Seoul National University Hospital, Republic of Korea, during a press conference. “Therefore we need stronger antiplatelet regimen the first month after PCI.”
There are two options for this, Kim said. A DDAT regimen, (150 mg clopidogrel and aspirin) is commonly used in high-risk PCI patients; however, in Asia, commonly cilostazol is added to dual-antiplatelet therapy (aspirin + 75 mg of clopidogrel)—what Kim et al deemed in the trial as triple antiplatelet therapy (TAT).
Because no previous trials have compared these two regimens, Kim et al conducted the HOST-ASSURE trial,a large randomized trial that used a 2 x 2 factorial design and enrolled 3,750 allcomers who received PCI.
The study also looked at the outcomes of two drug-eluting stents— platinum chromium everolimus-eluting stent (Promus Element) and the coating and a cobalt–chromium zotarolimus-eluting stent (Endevor Resolute). Kim said the results will be presented at next year’s meeting.
Cilostazol has been previously shown to prevent restenosis, vasodilation, improve lipid levels and protect the kidneys, Kim said.
During the HOST-ASSURE trial, 1,879 patients were randomized to receive TAT and 1,876 patients were randomized to receive DDAT. The entire patient cohort received between a 300 mg and 600 mg dose of clopidogrel plus a 300 mg dose of aspirin prior to PCI with TAT or without DDAT a loading dose of 20 mg of cilostazol. Those patients randomized to the TAT group also received a twice daily 100 mg dose of cilotazol for one-month post-procedure. Patients in the DDAT arm received a maintenance regimen of 150 mg of clopidogrel in addition to aspirin.
Kim et al used clinical outcomes (cardiac death, nonfatal MI, stroke and major bleeding) at one month as the study’s primary end point. Forty hospitals throughout Korea participated.
The study used a non-inferiority design, and is the largest clinical trial ever to be performed in South Korea, Kim noted.The primary end point occurred in 1.4 percent of patients in the DDAT group vs. 1.2 percent of those in the TAT arm.
Of the total cohort, one-third of patients were diabetic, one-third were smokers, one-third had stable angina and the average age was 62. Aspirin and clopidogrel was prescribed in more than 99 percent of patients at discharge.
“The non-inferiority of the trial was met,” Kim said. In fact, PLATO major bleeding rates were “exactly the same in both groups,” at 0.4 percent, which suggested safety, said Kim. Patients administered DDAT saw a slightly higher periprocedural MI event rate compared with those administered TAT, 0.69 percent vs. 0.37 percent, respectively. At one month, definite or probable stent thrombosis rates were also lower in patients administered TAT when compared with those administered DDAT, 0.21 percent vs. 0.37 percent, respectively.
In a per-protocol analysis, five MIs occurred in the 1,637 patients administered DDAT compared with zero MIs occurring in the 1,773 patients administered TAT.
Kim et al also performed a subgroup analysis based on age, sex, ACS, diabetes, renal dysfunction, and other factors, as part of the study evaluation. “There is no subgroup … that favors TAT or DDAT,” said Kim. “The results of the subanalysis are consistent with the results of all patients.”
Kim did report several study limitations:
- Event rates were lower than expected;
- Chance of under-reporting;
- Low rates of periprocedural MI; and
- Non-adherence to allocated treatments may have affected outcomes. Non-adherence rate was 91.6 percent in the TAT group and 86.5 percent in the DDAT group.
Kim concluded that adding cilostazol to DAPT was non-inferior to the double-dosing strategy of clopidogrel, according to the clinical outcomes reported at one month. “Both regimens are slightly stronger than the conventional dose.”
“There were no differences between the two treatment regimens regarding the individual components of the primary outcome,” he summed.
Some panelists questioned whether this strategy would be generalizable to a wider population, as this study focused on the Asian population. Additionally, they also questioned why Kim et al chose a non-inferiority trial design, as it is more challenging to interpret. In response, Kim said, “We tried to establish a more feasible … four-week regimen in this trial.
“TAT is more important than DDAT in platelet inhibition and for that reason I think there is sufficient rational to introduce TAT into practice,” Kim summed.