Serum uric acid levels during dual antiplatelet therapy with ticagrelor or clopidogrel: Results from a single-centre study.

BACKGROUND AND AIMS: New antithrombotic therapies have significantly improved the outcomes of patients with acute coronary syndrome (ACS), where the introduction of ticagrelor has provided the greatest mortality benefits. However, ticagrelor treatment has been associated with a potential increase in the serum uric acid (SUA) levels, which may influence endothelial dysfunction and prothrombotic status, thereby affecting the risk of acute cardiovascular events in patients requiring dual antiplatelet therapy (DAPT). The present study aimed to compare the impact of antiplatelet agents such as ticagrelor or clopidogrel on SUA levels and their effect on platelet reactivity. METHODS AND RESULTS: We included patients admitted for ACS or elective percutaneous coronary intervention (PCI) and discharged with ASA (acetylsalicylic acid; 100-160 mg) and clopidogrel (75 mg) or ticagrelor (90 mg twice a day). Chemistry was assessed at admission (baseline) and after a 30-90-day period of DAPT (together with platelet reactivity). The absolute and percentage variations of SUA after DAPT introduction were considered. Multiple-electrode aggregometry was used to assess platelet function. A total of 378 patients were enrolled, with 145 treated with aspirin and clopidogrel (AC) and 233 with aspirin and ticagrelor (AT). The AC patients were older (p = 0.003) and more often showed elective PCI as an indication to DAPT (<0.001); they received chronic therapy with ARB (angiotensin II receptor blocker; p = 0.001), nitrates (p = 0.044), CCB (calcium channel blocker; p = 0.005) and diuretics (p = 0.044). The AT patients displayed a higher percentage of ACS diagnosis (p < 0.001) and received chronic therapy with ACE (angiotensin-converting enzyme) inhibitors (p = 0.001), beta blockers (p = 0.001) and statins (p = 0.013). The AC patients displayed higher platelet reactivity at COL (collagen) test, ASPI test and ADP (adenosine diphosphate) test (p = 0.03, 0.001 and <0.001, respectively) and a higher percentage of HRPR (high residual platelet reactivity) in the ADP test (p = 0.001). No difference was found in the baseline uric acid and creatinine levels between AC and AT patients. At 30-90 days, a significant absolute and percentage increase in the SUA levels was found in AT as compared to AC patients (0.204 mg/dl vs. -0.165 mg/dl, p = 0.034; 6.26% vs. -0.005%, p = 0.018, respectively). Results were not influenced by variations in renal function. At multivariate analysis, in fact, ticagrelor therapy emerged as an independent predictor of increase in the uric acid levels (odds ratio (OR; 95% confidence interval (CI)) = 2.79 (1.66-4.67), p < 0.001). However, the variation in the SUA levels did not affect platelet reactivity or HRPR in both AC and AT patients. CONCLUSION: An increase in the SUA levels at 30-90 days was observed in patients receiving chronic DAPT with ticagrelor, but not clopidogrel treatment. However, the changes in the SUA levels do not influence platelet aggregation.

Uric acid and high-residual platelet reactivity in patients treated with clopidogrel or ticagrelor.

BACKGROUND AND AIM: High residual platelet reactivity (HRPR) is still an important challenge, despite the advent of new potent ADP-antagonists. Therefore it is of extreme importance to identify factors that can influence platelet activation. Serum uric acid (SUA) has been largely addressed in the past as a possible risk factor for coronary artery disease, with a possible association with platelets hyperreactivity. So far no studies have assessed the role of serum uric acid on the response to dual antiplatelet therapy. Therefore, the aim of our study was to evaluate the impact of uric acid levels on platelet function in patients treated with dual antiplatelet therapy (DAPT) with clopidogrel or ticagrelor. METHODS AND RESULTS: We scheduled for platelet function assessment at 30-90 days post-discharge patients treated with DAPT (ASA + clopidogrel or ticagrelor) for an ACS or elective percutaneous coronary intervention (PCI). Platelet function was assessed by whole blood impedance aggregometry (Multiplate(®)-Roche Diagnostics AG), HRPR was considered for ASPI test >862 AU(∗)min (for ASA) and ADP test values ≥417 AU* min (for ADP-antagonists). RESULTS: We included a total of 493 patients (262 were on ASA and clopidogrel and 231 on ASA and ticagrelor). Patients were divided according to quartiles of serum uric acid levels measured at the time of platelet aggregation assessment (Group 1 <4.6 mg/dL, n = 114; Group 2, 4.7-5.8 mg/dL, n = 133; Group 3, 5.9-6.8 mg/dL, n = 124; Group 4, >6.9, n = 122). Patients with higher uric acid levels were older, more often smokers, with history of hypertension and previous coronary artery bypass surgery and renal failure and were more often on therapy with diuretics at admission. Patients with higher SUA had higher triglycerides and fibrinogen. Uric acid levels did not influence ASPI, COL, TRAP and ADP tests. High residual platelet reactivity (HRPR) was observed in 1.5% of patients treated with ASA, with no difference according to SUA quartiles (p = 0.60), confirmed at multivariate analysis after correction for baseline confounders (adjusted OR[95%CI] = 1.05 [0.44-2.52], p = 0.90). HRPR for ADP-antagonists was observed in 23.6% of patients, with no difference according to SUA quartiles (p = 0.47); this result was confirmed also after correction for baseline confounders (adjusted OR[95%CI] = 1.04 [0.84-1.28], p = 0.73). Moreover, no association was found between HRPR and uric acid levels both among patients treated with clopidogrel (p = 0.35) or ticagrelor (p = 0.74), that was confirmed after correction for baseline confounding factors (adjusted OR[95%CI] = 1.18 [0.90-1.55], p = 0.23) and (adjusted OR[95%CI] = 0.96 [0.63-1.47], p = 0.85). The absence of association between SUA and platelet reactivity was confirmed at linear regression analysis both with clopidogrel (r = 0.03, p = 0.55) or ticagrelor (r = -0.01, p = 0.85). CONCLUSION: This is the first large study showing that in patients receiving DAPT, uric acid levels do not influence response to ticagrelor and clopidogrel or the effectiveness of ASA.

Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

UNLABELLED: ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor. BACKGROUND: The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged ≥ 70 years. RESULTS: Among 494 patients on DAPT, 224 (45.3%) were ≥ 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 ± 148.6 vs. 319.6 ± 171.1 vs. 347.3 ± 190.1 vs. 345.7 ± 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29-3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]). CONCLUSION: In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor.

Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.

BACKGROUND: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. METHODS: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. RESULTS: A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). CONCLUSIONS: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.