Ticagrelor, a platelet aggregation inhibitor for the potential prevention and treatment of arterial thrombosis and acute coronary syndromes

Ticagrelor is an orally active ADP P2Y12 receptor antagonist in development by AstraZeneca plc for the reduction of recurrent ischemic events in patients with acute coronary syndromes (ACS). Prior to the development of ticagrelor, thienopyridine compounds, such as clopidogrel, were the focus of research into therapies for ACS. Although the thienopyridines are effective platelet aggregation inhibitors, they are prodrugs and, consequently, exert a slow onset of action. In addition, the variability in inter-individual metabolism of thienopyridine prodrugs has been associated with reduced efficacy in some patients. Ticagrelor is not a prodrug and exhibits a more rapid onset of action than the thienopyridine prodrugs. In clinical trials conducted to date, ticagrelor was a potent inhibitor of ADP-induced platelet aggregation and demonstrated effects that were comparable to clopidogrel. In a phase II, short-term trial, the bleeding profile of participants treated with ticagrelor was similar to that obtained with clopidogrel; however, an increased incidence of dyspnea was observed - an effect that has not been reported with the thienopyridines. Considering the occurrence of dyspnea, and the apparent non-superiority of ticagrelor to clopidogrel, it is difficult to justify a clear benefit to the continued development of ticagrelor. Outcomes from an ongoing phase III trial comparing ticagrelor with clopidogrel in 18,000 patients with ACS are likely to impact on the future development of ticagrelor.

New drugs for the treatment of coronary artery syndromes

Background: Acute coronary syndromes are a major cause of mortality and morbidity. Objectives/Methods: The objective of this evaluation is to review the clinical trials of two new drugs being developed for the treatment of acute coronary syndromes. The first drug is the anti-coagulant otamixaban, and the trial compared otamixaban with unfractionated heparin and eptifibatide in acute coronary syndromes. The second drug is the anti-platelet ticagrelor, and the trial compared ticagrelor with clopidogrel in acute coronary syndromes. Results: In the SEPIA-ACS1 TIMI 42 trial, the primary efficacy endpoint occurred in 6.2% of subjects treated with unfractionated heparin and eptifibatide, and to a significantly lesser extent with otamixaban. In the PLATO trial, the primary efficacy endpoint had occurred less in the ticagrelor group (9.8%) than in the clopidogrel group (11.7%) at 12 months. Conclusions: Two new drugs for acute coronary syndromes, otamixaban and ticagrelor, have recently been shown to have benefits in subjects undergoing percutaneous interventions compared to the present standard regimens for this condition.

In-hospital mortality rates after a cemented femoral component for displaced neck of femur fractures

Aim This prospective cohort study investigated whether the use of preoperative anticoagulants is an independent risk factor for the outcomes of surgical treatment of patients with a neck of femur fracture. Methods Data was obtained from a prospectively collected database. All patients admitted for a neck of femur fracture between Nov 2010 and Oct 2011 were included. This resulted in three hundred twenty-eight patients with 330 neck of femur fractures. Four groups were defined; patients preoperatively (i) on aspirin (n = 105); (ii) on clopidogrel (n = 28); (iii) on warfarin (n = 30), and; (iv) without any anticoagulation history (n = 167, the control group). The non-warfarin group included the aspirin group, clopidogrel group and the control group. Primary outcome was the in-hospital mortality. Secondary outcomes were the postoperative complications, return to theatre and length of stay. Results Thirteen in-hospital deaths were identified, 4 deaths in the aspirin group, 1 death in the clopidogrel group, 2 deaths in the warfarin group and 6 deaths in the control group. No significant difference in the mortality rates was found between the different groups. Also in the secondary outcomes, no significant difference was found between the four groups. A trend to a higher wound complication rate for the warfarin group was detected. Conclusion The use of clopidrogel or aspirin pre operatively is not an influence on short term patient outcome for patients with a neck of femur fracture. Surgical procedures should not be delayed to reverse their influence.

Effects of anticoagulants on outcome of femoral neck fracture surgery

PURPOSE To review records of 330 patients who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy. METHODS Medical records of 235 women and 95 men aged 48 to 103 years (mean, 81.6; standard deviation [SD], 13.1) who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy were reviewed. 30 patients were on warfarin, 105 on aspirin, 28 on clopidogrel, and 167 were controls. The latter 3 groups were combined as the non-warfarin group and compared with the warfarin group. Hospital mortality, time from admission to surgery, length of hospital stay, return to theatre, and postoperative complications (wound infection, deep vein thrombosis, and pulmonary embolism) were assessed. RESULTS The warfarin and control groups were significantly younger than the clopidogrel and aspirin groups (80.8 vs. 80.0 vs. 84.2 vs. 83.7 years, respectively, p<0.05). 81% of the patients underwent surgery within 48 hours of admission. The overall mean time from admission to surgery was 1.8 days; it was longer in the warfarin than the aspirin, clopidogrel, and control groups (3.3 vs. 1.8 vs. 1.6 vs. 1.6 days, respectively, p<0.001). The mean length of hospital stay was 17.5 (SD, 9.6; range, 3-54) days. The overall hospital mortality was 3.9%; it was 6.7% in the warfarin group, 3.8% in the aspirin group, 3.6% in the clopidogrel group, and 3.6% in the control group (p=0.80). Four patients returned to theatre for surgery: one in the warfarin group for washout of a haematoma, 2 in the aspirin group for repositioning of a mal-fixation and for debridement of wound infection, and one in the control group for debridement of wound infection. The warfarin group did not differ significantly from non-warfarin group in terms of postoperative complication rate (6.7% vs. 2.7%, p=0.228) and the rate of return to theatre (3.3% vs. 1%, p=0.318). CONCLUSION It is safe to continue aspirin and clopidogrel prior to surgical treatment for femoral neck fracture. The risk of delaying surgery outweighs the peri-operative bleeding risk.