No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy

The risk for gastrointestinal bleeding from dual antiplatelet therapy (DAPT) with new antiplatelets (prasugrel/ticagrelor) compared to clopidogrel is unclear. Aim: To determine the risk and type of major (gastrointestinal bleeding requiring hospitalization) and minor (anemia and iron deficiency) gastrointestinal events with different types of DAPT. Methods: Retrospective observational cohort study of patients who started DAPT after percutaneous coronary intervention. Follow-up was censored after 12 months of DAPT, when a major gastrointestinal event occurred, or when DAPT was discontinued. Results: Among 1,327 patients (54.03% were treated with clopidogrel-based DAPT, 38.13% with ticagrelor-based DAPT, and 7.84% with prasugrel-based DAPT), 29.5% had at least one gastrointestinal event. Patients taking clopidogrel-DAPT were older, with more comorbidities, and higher gastrointestinal risk compared to those taking other DAPT regimens. Adjusted hazard ratios (HRs) showed no between-group differences in the risk for major (clopidogrel vs. new antiplatelets: HR 0.996; 95% confidence interval 0.497–1.996) and minor (HR 0.920; 0.712–1.189) gastrointestinal events. Most patients received proton pump inhibitors while on DAPT (93.3%) and after withdrawal (83.2%). Conclusion: Prasugrel- or ticagrelor-based DAPT was not associated with increased gastrointestinal bleeding risk when compared to clopidogrel-DAPT. New antiplatelets do not necessarily need to be restricted to patients with low gastrointestinal risk.

Clustered allocation as a way of understanding historical controls: Components of variation and regulatory considerations

There has been increasing interest in recent years in the possibility of increasing the efficiency of clinical trials by using historical controls. There has been a general recognition that in replacing concurrent by historical controls, the potential for bias is serious and requires some down-weighting to the apparent amount of historical information available. However, such approaches have generally assumed that what is required is some modification to the standard inferential model offered by the parallel group trial. In our opinion, the correct starting point that requires modification is a trial in which treatments are allocated to clusters. This immediately shows that the amount of information available is governed not just by the number of historical patients but also by the number of centres and of historical studies. Furthermore, once one accepts that external patients may be used as controls, this raises the issue as to which patients should be used. Thus, abandoning concurrent control has implications for many aspects of design and analysis of trials, including (a) identification, pre-specification and agreement on a suitable historical dataset; (b) an agreed, enforceable and checkable plan for recruiting the experimental arm; (c) a finalised analysis plan prior to beginning the trial and (d) use of a hierarchical model with sufficient complexity. We discuss these issues and suggest approaches to design and analysis making extensive reference to the partially randomised Therapeutic Arthritis Research and Gastrointestinal Event Trial study. We also compare some Bayesian and frequentist approaches and provide some important regulatory considerations. We conclude that effective use of historical data will require considerable circumspection and discipline.

Increased Incidence of Severe Gastrointestinal Events With First-Line Paclitaxel, Carboplatin, and Vorinostat Chemotherapy for Advanced-Stage Epithelial Ovarian, Primary Peritoneal, and Fallopian Tube Cancer

ObjectivesWe sought to assess the response rate and toxicity of paclitaxel, carboplatin, andvorinostat primary induction therapy for the treatment of advanced-stage ovarian carcinoma.MethodsPatients were treated with 6 cycles of weekly paclitaxel (80 mg/m2), carboplatin (6 times area under the curve), and vorinostat (200 mg) every 28 days according to an institutional review board–approved protocol. The subjects were eligible for response evaluation; in patients who achieved stable disease or better following the conclusion of primary induction chemotherapy, they were subsequently treated with a planned 12 cycles of paclitaxel (135 mg/m2) and vorinostat (400 mg) maintenance chemotherapy every 28 days.ResultsEighteen patients received a combined 90 cycles (median, 6 cycles; range, 1–6 cycles) of primary induction chemotherapy. Of the 18 subjects, 7 demonstrated a complete response, and 2 subjects exhibited a partial response (a total response rate of 50.0%). Eight patients also received a combined total of 50 cycles (median, 5 cycles; range, 1–12 cycles) of consolidation therapy. Grade 3/4 neutropenia and thrombocytopenia were observed in 9 (56.3%) and 2 (12.5%) patients. One patient (6.3%) developed grade 3 anemia, and another (6.3%) manifested a grade 3 neuropathy. Remarkably, we observed a significant gastrointestinal event (eg, bowel anastomotic perforation) in 3 patients, which effectuated the study’s closure.ConclusionsBecause the current study was prematurely terminated, we cannot derive a conclusive assessment regarding the efficacy of this treatment. Nevertheless, the high incidence of severe gastrointestinal toxicity warrants further consideration when using vorinostat in the adjuvant setting for patients who have undergone a bowel resection as part of their initial tumor debulking.