Low hemoglobin predicts high‐platelet reactivity and major cardiovascular ischemic events at long‐term follow‐up among ACS patients receiving dual antiplatelet therapy with ticagrelor

Abstract

Background Reduced levels of hemoglobin (Hb) represent an established marker of impaired outcomes and increased cardiovascular risk in patients with coronary artery disease, challenging the management of dual antiplatelet therapy (DAPT). However, while anemia has emerged as an independent predictor of suboptimal platelet inhibition in patients receiving clopidogrel, no study has so far evaluated the impact of Hb levels on high‐on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were the aim of the present study. Methods Patients on DAPT with ASA + Ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30–90 days post‐discharge. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition (HRPR‐high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome [MI], target vessel revascularization) at longest available follow‐up. Results We included 397 patients that were divided according to tertiles values of Hb (< 12.7, 12–7–14.09, ≥14.1 g/dl). Patients with lower Hb were older and displayed a more severe cardiovascular risk profile. Mean levels of platelet reactivity were enhanced in patients with lower Hb after stimulation with TRAP peptide (TRAP test, p = .03) and ADP (p = .02). Elevated platelet reactivity (HRPR) on Ticagrelor was more frequent among patients with reduced Hb (16.4% vs. 12% vs. 5.4%, p = .005, adjusted OR [95%CI] = 1.71[0.996;3.01], p = .056). At a mean follow‐up of 820.9 ± 553.4 days, 21.4% of the patients experienced the primary composite endpoint, with a higher rate of events in patients with lower Hb (27.6% vs. 22.6% vs. 13.5%, p = .006, adjusted HR [95%CI] = 1.51[1.12; 2.03], p = .006), mainly driven by a higher rate of recurrent ACS. After correction for baseline differences lower Hb tertiles but not HRPR emerged as independent predictor of MACE (adjusted HR [95%CI] = 0.98[0.50; 1.92], p = .95). Conclusions In the present study, we demonstrated that among patients on DAPT with ASA and ticagrelor after PCI for ACS, lower Hb levels are independently associated with a higher rate of HRPR and an increased rate of major ischemic events, and especially for recurrent ACS, although with no impact on survival. Neutral prognostic effect of HRPR was observed across Hb tertiles.

Association of ADP-Induced Whole-Blood Platelet Aggregation with Serum Low-Density Lipoprotein Cholesterol in Patients with Coronary Artery Disease When Receiving Maintenance Ticagrelor-Based Dual Antiplatelet Therapy

“…Accordingly, the complex multifactorial nature of elevated platelet reactivity when undergoing DAPT limited the extrapolation of specific results to different clinical scenarios. Nevertheless, all reported determinants of high residual platelet reactivity on ticagrelor-based DAPT, including higher serum LDL-c in the present study, were established or putative CV risk factors [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 28 , 33 ].…”

“…Notably, in neither one of those studies [18][19][20][21][22][23][24][25][26][27][28][29][30] correlated LDL-c or any parameter with increased platelet reactivity in patients treated with ticag DAPT. However, higher LDL-c, in addition to HbA1c, was associated wit…”

“…Notably, in neither one of those studies [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] correlated LDL-c or any other lipid parameter with increased platelet reactivity in patients treated with ticagrelor-based DAPT. However, higher LDL-c, in addition to HbA1c, was associated with increased platelet reactivity in mainly post-ACS subjects on prasugrel-based DAPT for 1–3 months [ 31 ], and higher pre-PCI LDL-c predicted future elevated platelet reactivity at 6 months of clopidogrel-based DAPT after elective PCI in univariate analysis, but not its multivariate form [ 32 ].…”

“…In a series of papers by the Novara Atherosclerosis Study Group, the investigators reported many correlates of elevated residual on-treatment platelet reactivity in patients undergoing DAPT with ticagrelor for 1–3 months, including advanced age [ 18 , 19 ], hypertension [ 19 ], T2DM (in particular with higher HbA1c) [ 20 ], higher neutrophil-to-lymphocyte ratio [ 21 ], lower Hb [ 22 ], decreased vitamin D [ 23 ], and increased homocysteine levels [ 24 ], whereas serum creatinine [ 25 ], uric acid [ 26 ], and BMI [ 27 ] were unrelated to platelet reactivity.…”

Diurnal Variability of Platelet Aggregation in Patients with Myocardial Infarction Treated with Prasugrel and Ticagrelor

“…Despite reaching statistical significance, these variables were responsible only for 6-7% of circadian variability in platelet inhibition and the clinical significance of these findings remains vague. Currently available data suggest that lower concentrations of hemoglobin are associated with a higher rate of HPR and an increased rate of recurrent ACS in patients treated with ticagrelor [47]. In ticagrelor-treated patients, mean platelet volume does not influence the risk of HPR; however, it is related with an increased rate of cardiovascular events in ACS patients [48,49].…”