By Michael H. Crawford, MD, Editor
SYNOPSIS: An extended six-year follow-up of the HOST-EXAM study revealed the consistent benefit of the primary endpoint of fewer major cardiovascular events and less bleeding with clopidogrel vs. low-dose aspirin monotherapy in post-percutaneous coronary intervention patients who were on dual antiplatelet therapy for one year.
SOURCE: Kang J, Park KW, Lee H, et al. Aspirin versus clopidogrel for long-term maintenance monotherapy after percutaneous coronary intervention: The HOST-EXAM extended study. Circulation 2023;147:108-117.
The authors of the Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy (HOST-EXAM) trial compared clopidogrel to low-dose aspirin monotherapy after percutaneous coronary intervention (PCI) for 24 months. After six to 18 months of dual antiplatelet therapy, researchers reported an associated with fewer cardiovascular adverse outcomes and bleeding. However, there was a numerical increase in all-cause deaths in the clopidogrel group, but it was not statistically significant.
Kang et al performed a post-trial extended follow-up for a median of six years. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction (MI), stroke, readmission for acute coronary syndrome (ACS), and major bleeding. The secondary endpoint was a composite of cardiac death, MI, ischemic stroke, ACS, stent thrombosis, or any bleeding. From 2014 to 2018, researchers entered 5,438 patients into the original trial and enrolled 4,717 patients in the extension study (the mean age was 63 years; 75% were men).
The primary endpoint occurred in 13% of the clopidogrel group and 17% of the aspirin group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; P < 0.001). The absolute risk reduction on clopidogrel was 4% and the number needed to treat was 24. The secondary thrombotic endpoint occurred in 8% of the clopidogrel group and 12% of the aspirin group (HR, 0.66; 95% CI, 0.55-0.79; P < 0.001). Any bleeding occurred in 4.5% of the clopidogrel group and 6% of the aspirin group (HR, 0.74; 95% CI, 0.57-0.94; P = 0.016). The all-cause death rate was similar between the two groups (6.2% vs. 6%). The authors concluded that after a six-year follow-up, among post-PCI patients without an adverse event in the first 12 months of dual antiplatelet therapy, clopidogrel compared to aspirin monotherapy was associated with fewer adverse clinical outcomes.
COMMENTARY
The HOST-EXAM extension study puts to rest the troubling finding of the initial HOST-EXAM study observation: the all-cause mortality rate was numerically higher but not statistically different with clopidogrel vs. aspirin monotherapy at 24 months. In the extension trial, not only was all-cause death not statistically different, there were fewer deaths. Kang et al replicated all other outcomes of the original trial, which demonstrates a consistent benefit of clopidogrel monotherapy for a median of six years. However, since antiplatelet therapy after PCI can be a lifelong proposition, longer follow-up data are desirable. Investigators plan on conducting a 10-year follow-up.
There are other issues not addressed in HOST-EXAM. Considering the demonstrated benefits of long-term, high-intensity statin therapy, it will be important to see if the results of HOST-EXAM persist over longer periods. Also, even though clopidogrel is generic in the United States, it is more expensive than aspirin. Other researchers should assess cost effectiveness. In addition, other studies of long-term adherence are needed. We know patients discontinue aspirin for a variety of reasons, but we have fewer data on clopidogrel adherence. In the HOST-EXAM extension, 13.5% of patients stopped aspirin mainly because of gastrointestinal upset and bleeding, whereas 8% discontinued clopidogrel. With newer stents, there are data to support earlier transition to monotherapy, but it is unclear what that should be. We now have other P2Y12 drugs at our disposal, such as ticagrelor and prasugrel. Would they perform better long term?
Meanwhile, there were weaknesses in HOST-EXAM extension to consider. Kang et al used an open-label design; the protocol did not dictate which drug to use as monotherapy (most patients took the previously assigned agent). This extension study was not powered for mortality, but no differences have been observed at this point. The authors did not test genetic resistance to clopidogrel, although that might not be critical. This was a relatively young East Asian (Korean) population, so the results may not apply to other groups. Perhaps the most important observation of HOST-EXAM is clopidogrel was superior for preventing thrombotic events and bleeding compared to aspirin. Considering all-cause mortality is not different with longer follow-up of this population, this concern from the initial report can be laid to rest. Converting to clopidogrel monotherapy after about 12 months of dual antiplatelet therapy in post-PCI patients is compelling.
An extended six-year follow-up of the HOST-EXAM study revealed the consistent benefit of the primary endpoint of fewer major cardiovascular events and less bleeding with clopidogrel vs. low-dose aspirin monotherapy in post-percutaneous coronary intervention patients who were on dual antiplatelet therapy for one year.
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