Randomized, Double-Blind, Active Comparator Pharmacodynamic Study of Platelet Inhibition with Crushed and Integral Formulations of Clopidogrel and Ticagrelor in Acute Coronary Syndrome.

BACKGROUND: Crushed formulations of specific antiplatelet agents produce earlier and stronger platelet inhibition. We studied the platelet inhibitory effect of crushed clopidogrel in patients with acute coronary syndrome (ACS) and its relative efficacy compared with integral clopidogrel, crushed and integral ticagrelor. OBJECTIVES: We aimed to compare the platelet inhibitory effect of crushed and integral formulations of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS). METHODS: Overall, 142 patients with suspected ACS were randomly assigned to receive crushed or integral formulations of clopidogrel or ticagrelor. Platelet inhibition at baseline and 1 and 8 h was assessed using the VerifyNow assay. High on-treatment platelet reactivity (HTPR) ≥ 235 P2Y12 reaction units (PRUs) 1 h after the medication loading dose was also determined. RESULTS: The PRU and percentage inhibition median (interquartile range) at 1 h for the different formulations were as follows: crushed clopidogrel: 196.50 (155.50, 246.50), 9.36 (- 1.79, 25.10); integral clopidogrel: 189.50 (159.00, 214.00), 2.32 (- 2.67, 19.89); crushed ticagrelor: 59.00 (10.00, 96.00), 75.53 (49.12, 95.18); and integral ticagrelor: 126.50 (50.00, 168.00), 40.56 (25.59, 78.69). There was no significant difference in PRU or percentage platelet inhibition between the crushed and integral formulations of clopidogrel (p = 0.990, p = 0.479); both formulations of ticagrelor were superior to the clopidogrel formulations (p < 0.05). On paired comparison, crushed ticagrelor showed robust early inhibition of platelets compared with the integral formulation (p = 0.03). Crushed clopidogrel exhibited the maximal HTPR of 34.3%, but was < 3% for both formulations of ticagrelor. CONCLUSIONS: The platelet inhibitory effect of crushed clopidogrel is not superior to integral preparation in patients with ACS. Crushed ticagrelor produced maximal platelet inhibition acutely. HTPR rates in ACS are similar and very low with both formulations of ticagrelor, and maximal with crushed clopidogrel. Clinical Trials Registry of India identifier number CTRI/2020/06/025647.

Clinical utility of activated partial thromboplastin time clot waveform analysis and thrombin generation test in the evaluation of bleeding phenotype in Hemophilia A.

CONTEXT: Hemophilia A is classified as mild, moderate, and severe based on Factor VIII levels (FVIII). Clot-based assays only detect initiation of thrombin generation, hence FVIII levels may not accurately predict the bleeding risk in all hemophilia patients. The entire process of thrombin generation as measured by global hemostasis tests like activated partial thromboplastin time clot waveform analysis (APTT CWA) and thrombin generation test (TGT) may reflect the actual bleeding phenotype. AIMS: To assess the utility of TGT and CWA as a screening tool to identify bleeders and to evaluate the bleeding phenotype in Hemophilia A. SETTINGS AND DESIGN: Prospective, observational study of 147 consecutive patients referred for coagulation workup. SUBJECTS AND METHODS: Bleeding assessment tool was used to identify bleeders. Patients were classified as severe and nonsevere bleeders based on clinical criteria. TGT was performed by calibrated automated thrombogram, CWA by photo-optical coagulometer and factor levels by one stage clot-based assays. STATISTICAL ANALYSIS USED: The Kruskal-Wallis test with post-hoc analysis was done to examine the difference in CWA/TGT parameters amongst hemophilia classified by FVIII levels. Receiver operating characteristic (ROC) analysis was performed to estimate the diagnostic accuracy of CWA and TGT in discriminating between clinically severe vs nonsevere bleeders. RESULTS: Using ROC derived cut-offs of min1, min2 and peak height of thrombin (PH), the sensitivity (min1:91.67%, min2:91.67%, PH: 97.22%, FVIII: 86.11%) and specificity (min1:100%, min2:100%, PH: 90.91%, FVIII: 90.91%) of CWA/TGT was superior to FVIII to distinguish between clinically severe vs nonsevere bleeders. Phenotypic heterogeneity of bleeding severity was identified in our study population. Clinical severity correlated with CWA/TGT parameters instead of FVIII levels. CONCLUSIONS: CWA and TGT are more effective tools than conventional factor assays to identify clinically severe bleeders and tailor prophylaxis as per bleeding phenotype.