Efficacy and safety of apixaban for primary prevention in gastrointestinal cancers: A post-hoc analysis of the AVERT trial.

BACKGROUND: Recent trials have demonstrated that thromboprophylaxis using direct oral anticoagulants is effective but associated with a higher rate of major bleeding in intermediate-to-high risk (Khorana score ≥ 2) patients with cancer initiating systemic chemotherapy. Patients with gastrointestinal cancer may be at higher risk of major bleeding complications. We sought to assess the efficacy and safety of using thromboprophylaxis with apixaban in this patient population. METHODS: This is a post-hoc analysis of the AVERT trial, which was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was objectively documented venous thromboembolism within 180 days of randomization. The primary safety outcome was a major bleeding episode. Time-to-event analyses were performed in patients with gastrointestinal cancers (upper gastrointestinal, pancreatic/hepatobiliary and colorectal cancers). RESULTS: A total of 130 patients from the original AVERT trial were included, with 65 patients allocated to each of the apixaban and placebo groups. VTE occurred in 3 (4.6%) patients in the apixaban group and 13 (20%) patients in the placebo group (HR: 0.27; 95% CI: 0.13-0.54; p = 0.0002). Major bleeding occurred in 2 (3.1%) patients in the apixaban group and 1 (1.5%) patient in the placebo group (HR 2.39, 95% CI 0.29-19.78, p = 0.42). None of the major bleeding events occurred in patients with upper gastrointestinal or colorectal cancers. CONCLUSION: Primary thromboprophylaxis with apixaban therapy seems to be safe and effective in patients with gastrointestinal cancers. Major bleeding complications are uncommon in our cohort. (Funded by the CIHR and Bristol-Myers Squibb-Pfizer Alliance; NCT02048865).

The Dipeptidyl Peptidase 4 Substrate CXCL12 Has Opposing Cardiac Effects in Young Mice and Aged Diabetic Mice Mediated by Ca2+ Flux and Phosphoinositide 3-Kinase γ.

Blood glucose-lowering therapies can positively or negatively affect heart function in type 2 diabetes, or they can have neutral effects. Dipeptidyl peptidase 4 (DPP-4) inhibitors lower blood glucose by preventing the proteolytic inactivation of glucagon-like peptide 1 (GLP-1). However, GLP-1 is not the only peptide substrate of DPP-4. Here, we investigated the GLP-1-independent cardiac effects of DPP-4 substrates. Pointing to GLP-1 receptor (GLP-1R)-independent actions, DPP-4 inhibition prevented systolic dysfunction equally in pressure-overloaded wild-type and GLP-1R knockout mice. Likewise, DPP-4 inhibition or the DPP-4 substrates substance P or C-X-C motif chemokine ligand 12 (CXCL12) improved contractile recovery after no-flow ischemia in the hearts of otherwise healthy young adult mice. Either DPP-4 inhibition or CXCL12 increased phosphorylation of the Ca2+ regulatory protein phospholamban (PLN), and CXCL12 directly enhanced cardiomyocyte Ca2+ flux. In contrast, hearts of aged obese diabetic mice (which may better mimic the comorbid patient population) had diminished levels of PLN phosphorylation. In this setting, CXCL12 paradoxically impaired cardiac contractility in a phosphoinositide 3-kinase γ-dependent manner. These findings indicate that the cardiac effects of DPP-4 inhibition primarily occur through GLP-1R-independent processes and that ostensibly beneficial DPP-4 substrates can paradoxically worsen heart function in the presence of comorbid diabetes.

Incentivizing health care behaviors in emerging adults: a systematic review.

PURPOSE: For emerging adults with chronic medical diseases, the transition from pediatric to adult health care is often a time of great upheaval, commonly associated with unhealthy self-management choices, loss to follow-up, and adverse outcomes. We conducted a systematic review to examine the use of incentive strategies to promote positive health-related behaviors in young adults with chronic medical diseases. METHODS: The Medline, CINAHL, Embase, PsycInfo, and Cochrane databases were searched through June 2014. Studies of any design where an incentive was used to achieve a target behavior or outcome in a pediatric or emerging adult population (age <30 years) with chronic medical conditions including addictions, were included. RESULTS: A total of 26 studies comprising 10,880 patients met our inclusion criteria after screening 10,305 abstracts and 301 full-text articles. Of these studies, 20 examined the effects of behavioral incentives on cigarette smoking or substance abuse, including alcohol; four studies explored behavioral incentives in the setting of HIV or sexual health; and two articles studied individuals with other chronic medical conditions. Seventeen articles reported a statistically significant benefit of the behavioral incentive on one or more outcomes, although only half reported follow-up after the incentive period was terminated. CONCLUSION: While the majority of studies reported positive outcomes, these studies focused on promoting the cessation of adverse behaviors rather than promoting positive behaviors. In addition, conclusions were limited by the high risk of bias present in the majority of studies, as well as lack of follow-up after the incentive period. Whether behavioral incentives facilitate the adoption of positive health choices in this population remains to be determined.