The antiplatelet agent indobufen was noninferior to aspirin in combination with clopidogrel for dual antiplatelet therapy (DAPT) at 1 year after percutaneous coronary intervention (PCI), with similar efficacy and some indication of reduced bleeding, mostly minor events.
“Indobufen plus clopidogrel DAPT for 12 months is noninferior in the 1-year composite of efficacy and safety outcomes compared to aspirin plus clopidogrel dual antiplatelet therapy,” lead author Junbo Ge, MD, from the department of cardiology at Zhongshan Hospital, Fudan University in Shanghai, China, concluded in his presentation of the results.
“In patients with the need for DAPT, indobufen could be recommended as the alternative to aspirin when there is an intolerance or allergy,” Ge told theheart.org | Medscape Cardiology. “Moreover, this trial provides an important insight that could aid in decision-making for the optimal DAPT strategy in patients at high bleeding risk.”
Results of the OPTION trial were presented November 6 at the American Heart Association Scientific Sessions 2022 and published online simultaneously in Circulation.
Dual antiplatelet therapy is standard care following PCI, but some adverse noncardiac effects of aspirin, such as allergy and intolerance limits its use in clinical practice, Ge noted.
Indobufen is already approved in China by the National Medical Products Administration for the treatment of atherosclerotic cardiovascular disease but is not currently approved for use in the United States by the Food and Drug Administration.
It is an orally active antiplatelet agent that reduces the production of platelet thromboxane by inhibiting cyclooxygenase-1 (COX-1), Ge said. “Unlike aspirin, indobufen reversibly acetylates COX-1 with little impact on prostacyclin production,” he noted. Impairment of prostacyclin production is the main cause of the gastrointestinal adverse effects associated with aspirin.
Further, studies showed that, “indobufen caused a comparable inhibition platelet aggregation to that of aspirin and its effect diminished faster,” Ge added. “These results indicated that indobufen was associated with better platelet selectivity, tolerability, and benefit/risk profile.”
OPTION was a randomized, open-label, noninferiority trial comparing indobufen-based DAPT, using 100 mg twice daily of indobufen plus 75 mg/day of clopidogrel for 12 months, with conventional DAPT, using 100 mg/day of aspirin plus 75 mg/day of clopidogrel for 12 months.
Between January 2018 and October 2020, 4551 patients with negative cardiac troponin undergoing drug-eluting stent implantation at one of 101 centers in China were randomly assigned 1:1 to indobufen-based (n = 2258) or aspirin-based (n = 2293) DAPT.
The primary endpoint was a 1-year composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), ischemic stroke, definite or probable stent thrombosis, or Bleeding Academic Research Consortium (BARC) criteria type 2, 3, or 5 bleeding.
Results showed primary endpoint events occurred in 101 (4.47%) patients on indobufen-based DAPT, compared with 140 (6.11%) on conventional aspirin-based DAPT for an absolute difference of –1.63% (P for noninferiority < .001), with a hazard ratio of 0.73 (95% CI, 0.56 – 0.94; P = .015).
The secondary efficacy endpoint, a combination of cardiovascular death, nonfatal MI, ischemic stroke, and stent thrombosis occurred in 1.51% on indobufen-based DAPT vs 1.40% of patients on aspirin-based DAPT, a nonsignificant difference (HR, 1.08; 95% CI, 0.67 – 1.75; P = .757).
For the secondary safety endpoint, though, there was significantly more events on the combined endpoint of BARC type 2, 3, or 5 bleeding at 2.97% in the indobufen-based DAPT group vs 4.71% in the aspirin-based group.
Breaking down the types of bleeding, it became clear that the reduction in overall bleeding was driven by a significant reduction in BARC type-2, or minor bleeding events, that occurred in 1.68% of indobufen-based DAPT group vs 3.49% of those on aspirin-based DAPT (P < .001). There were no significant differences seen on more severe bleeding events between groups.
Revived Interest
Invited discussant for the presentation was Stefanie Schüpke, MD, German Heart Center Munich in Munich, Germany.
She pointed out that aspirin is an irreversible inhibitor of COX-1 and inhibits platelet function, “for the whole lifespan of the platelet. On the other hand, indobufen is a reversible COX-1 inhibitor, with platelet function returning to normal within 24 hours, which requires therefore a twice-daily dosing regimen.”
The higher platelet selectivity and fewer extra-platelet effects because prostacyclin production is less affected by indobufen, “has several theoretical advantages,” she said, including less gastrointestinal injury.
“In the last century, indobufen has been tested in several indications, including patients with cerebrovascular accident, atrial fibrillation, or at increased risk of thromboembolic events post-CABG and in patients with peripheral artery disease,” she said, although the maximum number of patients in these trials was 1632.
The OPTION trial has now compared indobufen with aspirin after successful drug eluting stent implantation in 4551 biomarker-negative patients, she said. At 1 year, indobufen was noninferior to aspirin on the composite endpoint of bleeding and ischemic complications.
“The authors should be congratulated for performing the largest randomized comparison of indobufen with aspirin,” she said. However, the trial was open label, the event rates were lower than expected, and the advantage of indobufen was “confined to less than moderate bleeding events.”
In addition, DAPT duration in this study was 12 months, which is longer than currently recommended for elective PCI, she noted. “If you look at the curves, you can see that the benefit of indobufen starts at about 6 weeks after PCI, the timepoint around which removal of aspirin is becoming a standard after elective PCI.”
Based on the results of the OPTION trial, “indobufen is an alternative to aspirin in biomarker-negative patients undergoing PCI with drug-eluting stents and treated with clopidogrel, particularly in cases of aspirin allergy or intolerance,” Schüpke said.
Still, “the additional value of indobufen compared to placebo after the periprocedural use of aspirin remains unclear, and the reversible and short action of indobufen requires a twice-daily regimen and high compliance of the patient,” she added.
“Since the first publication on indobufen in 1979, there was a peak in manuscripts in the 1990s, but I’m sure that there will be some kind of revival after the OPTION trial,” Schüpke concluded.
Also commenting for theheart.org | Medscape Cardiology was Dipti Itchhaporia, MD, Eric & Sheila Samson endowed chair in cardiovascular health, director of disease management for Hoag Heart and Vascular Institute, associate clinical professor at University of California, Irvine, and immediate past president of the American College of Cardiology.
Itchhaporia said she was not familiar with this agent, but nevertheless found the results “intriguing.”
“The whole reason they did this study was to say, ‘Is there something better than aspirin?'” she said. Patients can have intolerance or allergy to aspirin, and an agent with better platelet selectivity may not have those issues. While the results looked good in terms of both the primary and secondary endpoints, she would want to have more information on the drug itself, on its cost, and to see these results replicated in other studies.
“This is not a small trial, over 2000 patients in each arm, so I think it’s intriguing,” she added. Still, “I think I just need a little more information and to process this one.”
Ge noted that another trial of indobufen, the INSURE trial, is currently underway to evaluate whether indobufen is noninferior to aspirin in reducing recurrent stroke at 3 months in patients with moderate to severe ischemic stroke.
The study was sponsored by Hangzhou Zhhongmei Huadong Pharmaceutical Co Ltd and supported by Shanghai Clinical Research Center for Interventional Medicine and Clinical Research Special Fund of Zhongshan Hospital Fudan University. The authors have disclosed no relevant financial relationships.
American Heart Association (AHA) 2022 Scientific Sessions: Abstract 2022-LBS-19536-AHA. Presented November 6, 2022.
Circulation. Published online November 6, 2022. Full text
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