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For patients with a drug eluting stent who complete the first 6 to 18 months of dual antiplatelet therapy, continuing with long-term clopidogrel monotherapy was associated with a significantly reduced risk for both ischemic events and major bleeding compared with aspirin monotherapy in the HOST-EXAM randomized trial.

Dr Hyo-Soo Kim

“These data confirm our working hypothesis that long-term maintenance antiplatelet monotherapy with clopidogrel produces better outcomes than aspirin in patients who are adverse event–free at 1 year after coronary stenting,” said Hyo-Soo Kim, where to buy generic baclofen online no prescription MD, PhD, professor of internal medicine at Seoul National University Hospital, Seoul, South Korea, and lead author of the study.

Kim presented the results of the South Korean HOST-EXAM study on May 16 at the virtual American College of Cardiology (ACC) 2021 Scientific Session. The study was was simultaneously published in The Lancet.

The trial randomly assigned 5530 patients who had received dual antiplatelet therapy without clinical events for 6 to 18 months after drug-eluting stenting to receive either monotherapy with clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months.

The primary endpoint, a composite of all-cause death, nonfatal myocardial infarction (MI), stroke, readmission due to acute coronary syndrome (ACS), and Bleeding Academic Research Consortium (BARC) bleeding type ≥3, occurred in 5.7% of patients in the clopidogrel group and 7.7% in the aspirin group, a 27% relative reduction with clopidogrel (hazard ratio [HR], 0.73; P = .0035).

Results also showed that clopidogrel reduced both ischemic endpoints and bleeding endpoints compared with aspirin.

The secondary composite thrombotic endpoint of cardiac death, nonfatal MI, stroke, readmission due to ACS, or definite or probable stent thrombosis occurred in 3.7% of patients in the clopidogrel group and 5.5% of patients in the aspirin group (HR, 0.68; P = .0028). The number needed to treat to prevent one thrombotic event was 59.

Any bleeding (BARC type ≥2) occurred in 2.3% of patients in the clopidogrel group and 3.3% of patients in the aspirin group (HR, 0.70; P = .036), giving a number needed to treat to prevent one bleeding episode of 111.

Kim reported that most of the difference in bleeding events between the two groups was in regard to severe bleeding (BARC type 3C), including intracranial bleeds or intraocular bleeds that could lead to blindness. Gastrointestinal bleeding was also reduced with clopidogrel.

Particular endpoints that were reduced with clopidogrel included nonfatal MI (0.7% vs 1.0%), stroke (0.7% vs 1.6%), hemorrhagic stroke (0.2% vs 0.6%), readmission for ACS (2.5% vs 4.1%), and major bleeding (BARC ≥3; 1.2% vs 2.0%).

All-cause death was numerically higher in the clopidogrel group (1.9% vs 1.3%), although this was a nonsignificant difference.

Kim explained that current treatment guidelines recommend a dual antiplatelet regimen of 6 to 12 months after stenting, with monotherapy thereafter. But the optimal single-antiplatelet agent for long-term maintenance therapy has been unclear.

“Our results may be useful in helping physicians to select antiplatelet monotherapy for patients who are in the chronic stable phase after coronary stenting,” he concluded.

“A Very Important and Impactful Trial”

The designated discussant of the study at the ACC presentation, Cindy Grines, MD, said this was “a very important and impactful trial” that showed “a fascinating and provocative result,” despite a lower-than-expected event rate.

The results are similar to those of the CAPRIE trial, conducted over 20 years ago, of clopidogrel vs aspirin for secondary prevention, but in that study, aspirin was administered at a dose of 325 mg, noted Grines, who is chief scientific officer of the Northside Cardiovascular Institute in Atlanta, Georgia.

“To show a reduction of bleeding vs aspirin at a dose of 100 mg is even more impressive and very surprising,” she said.

Grines asked Kim whether he thought the results would be applicable outside of Asia, particularly in the United States, where there is a much greater degree of racial diversity and where obesity rates are higher.

“There is definitely a difference in the bleeding thrombosis balance between Asians and Caucasians, but clopidogrel resistance is less of an issue in Caucasians, so I would think the results should be applicable to them,” he replied.

Discussing the HOST EXAM study at an ACC press conference, Claire Duvernoy, MD, professor of medicine at the University of Michigan, Ann Arbor, Michigan, described the trial as “very provocative and potentially practice changing.”

“Aspirin has been around for hundreds of years and has become the cornerstone of therapy in the struggle to defeat coronary disease. It really is the bedrock of the therapies we use, and yet we all know that it comes with a significant cost in that it can be poorly tolerated in terms of gastrointestinal side effects and has significant bleeding risks,” Duvernoy noted. “This trial is another important finding in our search for alternatives.”

She said the study showed that patients whose conditions have been stable after placement of a stent can be safely and effectively transitioned from dual antiplatelet therapy to monotherapy with clopidogrel.

Duvernoy noted that clopidogrel monotherapy is not used much in the United States. “In my practice, I don’t use clopidogrel very often as monotherapy. I tend to only use it in patients who cannot tolerate aspirin. Most of us in the US use aspirin as long-term monotherapy after stent placement,” she added. “This is going to be a fascinating alternative.”

On the issue of applying the results of HOST-EXAM to non-Asian populations, Duvernoy said she thought this would be possible.

“The Korean population studied in this trial has a high prevalence of the clopidogrel loss-of-function allele, which would have suggested that clopidogrel would be less effective, and yet the study found it to be more efficacious and safer,” she noted. “To me, that suggests that we can apply these results to other populations as well. While I would like to see this strategy confirmed in multiethnic populations, to me, this is very encouraging.”

Duvernoy also raised the question of whether patients who are receiving long-term clopidogrel monotherapy could safely undergo surgery without having to first stop taking their medication.

“We have slowly become comfortable about operating on patients on aspirin, but I have yet to see a surgeon who is comfortable operating on patients who are taking dual antiplatelet therapy or clopidogrel monotherapy,” she said. “While this study certainly suggests that bleeding risk is not higher and indeed may be lower with clopidogrel, whether this also applies to perioperative bleeding is a critical question that will have to answered to allow us to use this therapy on a widespread basis.”

Asked about the fact that the all-cause death rate was higher in the clopidogrel group, Kim noted that the numbers of noncardiac and cancer deaths were numerically higher in the clopidogrel group. He wondered whether this could have been due to aspirin being linked to a lower mortality from colorectal cancer or was just the play the chance.

“The higher numerical rate of these events in our study did not reach statistical significance, so we don’t have any conclusive opinion on this,” he stated.

The researchers will continue to follow the patients in this study for up to 10 years. “With such long-term follow-up, we should be able to get some more insight on this,” Kim added.

Also commenting on the results, Deepak Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart and Vascular Center, Boston, Massachusetts, said he thought the numerical increase in all-cause death probably was the play of chance.

“The much larger CAPRIE trial randomized high-risk secondary prevention patients to aspirin or clopidogrel and found a reduction in ischemic events favoring clopidogrel, a reduction in hospitalization for GI bleeding with clopidogrel, and no difference in mortality or cancer,” Bhatt said.

“So that was a larger and longer-term study in which the ischemic and bleeding outcomes mirrored the results of this trial, but there was no mortality or cancer concern, so I would say this is probably the statistical play of chance. But certainly, a longer-term follow-up will be very interesting.”

The HOST-EXAM trial was funded by grants from funding a consortium of four Pharmaceutical Companies (ChongKunDang, SamJin, HanMi, and DaeWoong) and by grants from the Patient-Centered Clinical Research Coordinating Center and Korea Health Technology R&D Project, which is funded by the South Korea Ministry of Health and Welfare. Kim has received research grants or speaker’s fees from Medtronic, Abbott Vascular, Edwards Life Science, Boston Scientific, Terumo, Biotronik and Dio, AmGen, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, and Boehringer Ingelheim.

American College of Cardiology (ACC) 2021 Scientific Session: Presented May 16, 2021.

Lancet. Published online May 16, 2021. Full text

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