Double‐Dose Versus Standard‐Dose Clopidogrel According to Smoking Status Among Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Abstract

BackgroundPrior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel (“smoker's paradox”). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear.Methods and ResultsWe analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double‐dose (600 mg day 1;150 mg days 2–7; then 75 mg daily) versus standard‐dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double‐ versus standard‐dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double‐ versus standard‐dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50–0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80–1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48–1.24, P=0.28), whereas in nonsmokers, the double‐dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37–2.60, P<0.0001). Double‐dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24–0.71) and nonsmokers (HR 0.63, 95% CI, 0.42–0.93; P for interaction=0.19).ConclusionsIn smokers, a double‐dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452.

Clopidogrel Pharmacokinetics in Malaysian Population Groups: The Impact of Inter-Ethnic Variability

“…Under these revised dosing conditions, the percentage of subjects with a clopi-H4 C max below the minimum therapeutic concentration decreased to 12% (Malay) and 14% (Malaysian Chinese) ( Figure 13 ). A number of previous clinical studies have considered the high dose versus standard dose clopidogrel treatment regimens, particularly for CYP2C19 PM, and identified no significant clinical concerns, with improved inhibition of platelet aggregation and clinical outcomes [ 73 , 74 , 75 , 76 ], and our simulations further agreed with these published findings. Thus, a 600 mg loading dose followed by a 150 mg maintenance dose may be appropriate for confirmed CYP2C19 PM Malay and Malaysian Chinese patients, particularly where platelet response is poor.…”

No Paradoxical Effect of Smoking Status on Recurrent Cardiovascular Events in Patients Following Percutaneous Coronary Intervention: Thai PCI Registry

“…There is evidence that current cigarette smoking is an independent risk factor for subacute stent thrombosis ( 38 ). Doubling the dose of clopidogrel ( 39 ) or switching to more potent P2Y 12 inhibitors ( 40 , 41 ) may overcome a potential smoking cessation paradox in patients who stopped smoking after PCI. Further studies are required to determine the optimal antiplatelet strategy for stented patients who effectively quit smoking during clopidogrel treatment.…”

Research Article CYP2C19*2 polymorphism influenced response to clopidogrel treatment but was not related to restenosis in atherosclerotic smokers

“…Cigarettes have several influences on coagulation; one of them is endothelial dysfunction, it delays endothelial healing, thus leaving the smoker who undergoes stent implantation to be more susceptible to in-stent restenosis (Bossard, 2017). In 2017, Bossard and collaborators analyzed smoking in stent patients, where there was no statistically significant difference between smoking and the need for stenting.…”