Predictors of high on-clopidogrel platelet reactivity in patients with acute coronary syndrome

Abstract

High on-clopidogrel platelet reactivity (HPR) is a predictor of ischemic events after percutaneous coronary intervention. We conducted a prospective cohort study to identify variables related to HPR in acute coronary syndrome patients who are at high thrombotic risk. We enrolled 463 patients undergoing urgent coronary angiography. Platelet reactivity was measured 12-36 hours after 600 mg clopidogrel loading with multiple electrode aggregometry (Multiplate® analyzer, Roche, Basel, Switzerland, 6.4 µM ADP). HPR was defined by the consensus cut-off area under the curve >46 U. The rate of HPR was 16.0%. We analyzed simple clinical and laboratory parameters with backward multivariate logistic regression and identified the following predictors of HPR: platelet count (per G/L, OR: 1.0073, 95% CI: 1.0035-1.0112, p = 0.0002), CRP level (per mg/L, OR: 1.0077, 95% CI: 1.0016-1.01372, p = 0.01), and active smoking (OR: 0.51, 95% CI: 0.29-0.89, p = 0.02). We developed and internally validated a risk prediction model demonstrating moderate discriminative capacity (area-under-the-receiver operating characteristic curve = 0.67). In conclusion, we found a relatively low rate of high on-clopidogrel platelet reactivity (16.0%) even in an acute patient cohort. HPR measured by Multiplate was associated with high platelet count and CRP level on admission and was inversely related to active smoking. The model with rapidly available simple parameters might help to identify individuals at risk for HPR in the acute setting.

Response to clopidogrel therapy in patients after PCI changes over time as evidenced by different platelet function tests

“…The same link was demonstrated between platelet count and HPR phenomenon in another study. 12 On the contrary, we were not able to confirm the finding of Reed et al, 38 who demonstrated that smokers treated with clopidogrel exhibited reduced platelet reactivity and were less likely to have HPR than nonsmokers. Most reasonably, it could be explained by a relatively small size of our group.…”

“…This phenomenon typically occurs on clopidogrel therapy and can be partially attributed to the presence of diabetes, genetic polymorphisms, overweight, platelet count, C-reactive protein (CRP) level, reduced renal function, active smoking, older age, or acute coronary syndrome. [10][11][12][13][14][15][16][17][18] It is independently associated with a 2-to 5-fold higher risk of recurrent ischemic events compared with that in good responder to clopidogrel. However, this is only applicable to the whole groups of HPR patients, as all available PFTs have a low positive predictive value for individual risk estimation.…”

Influence of smoking on the antiplatelet effect of clopidogrel differs according to clopidogrel dose: Insights from the GRAVITAS trial

“…An analysis of the CROSS‐VERIFY (Measuring Clopidogrel Resistance to Assure Safety After PCI using VerifyNow) cohort not only found that smokers had significantly lower OTR that non‐smokers at baseline, but also that the level of OTR and frequency of high OTR in patients who quit smoking ( n = 77) rose significantly compared to persistent smokers at 1 month ( n = 105) . A slightly larger study ( n = 139 smokers) recently reported a lower rate of high OTR on clopidogrel among smokers compared to non‐smokers, and a separate study of patients with acute coronary syndrome found active smoking to be independently associated with lower risk of high OTR (OR 0.51, P = 0.02) . Further, our results are consistent with the PARADOX (The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Clopidogrel and Prasugrel) study, which randomly assigned smokers ( n = 54) and nonsmokers ( n = 56) with stable coronary artery disease to clopidogrel 75 mg or prasugrel 10 mg for 10‐days, followed by a 14‐day washout and treatment cross‐over .…”

“…Cigarette smoking enhances the generation of the active metabolite of clopidogrel by inducing CYP1A2 activity . Several studies suggest that there may be a “smokers’ paradox,” as although smoking has many negative effects on cardiovascular health, smokers have greater platelet inhibition and lower rates of high OTR when compared to non‐smokers on clopidogrel . Consistent with this observation, the CLARITY—TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28), CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), and CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trials all suggested that the clinical benefit of clopidogrel might be greater in smokers compared to non‐smokers .…”

Effects of Smoking on Volume, Conductivity and Scatter Parameters of Leukocytes

“…Although its cause and mechanism are not clearly known, acute smoking leads to an increase in leukocyte, eosinophil and platelet counts in peripheral blood (7). Several studies have indicated that the markers of white blood cell differential count and platelet activity are impaired by smoking (8,9).…”