2 Minute Medicine Rewind December 11, 2018
Apixaban to Prevent Venous Thromboembolism in Patients with Cancer
The risk of venous thromboembolism (VTE) is significantly increased in patients with active cancer. While parenteral prophylactic anticoagulation has been shown to reduce the risk of VTE in cancer patients, its use is associated with an increased risk of major bleeding and the inconvenience of daily injections. Direct oral anticoagulants (DOACs) offer important advantages over parenteral agents, with a recent phase 2 trial suggesting that apixaban, an oral factor Xa inhibitor, may be used safely and effectively in this patient population. In this randomized controlled trial, 574 patients with newly diagnosed cancer or progression of known cancer starting a new course of chemotherapy were randomly assigned to receive twice daily apixaban (2.5 mg) or placebo to study the impact on the incidence of VTE within the first 180 days of treatment. Researchers found that the incidence of VTE was significantly less in the apixaban group (4.2%) compared to the placebo group (10.2%) (HR 0.41, 95% CI 0.26 to 0.65, p<0.001). During the treatment period, VTE was also less frequent in the apixaban group (1.0%) compared to the placebo group (7.3%) (HR 0.14, 95% CI 0.05 to 0.42). In the modified intention-to-treat analysis, major bleeding was more common in the apixaban group (HR 2.00, 95% CI 1.01 to 3.95, p=0.046). However, during the treatment period, there was no significant difference in rates of major bleeding between the two groups (HR 1.89, 95% CI 0.39 to 9.24). In summary, results from this study indicate that apixaban may reduce the rate of VTE in cancer patients initiating chemotherapy, although not without an increased rate of bleeding events when compared to placebo.
Aortic stenosis is the most common valvular disease in elderly patients, and may result in left ventricular remodeling and diastolic dysfunction. Renin-angiotensin system (RAS) inhibitors have been shown to reduce left ventricular remodeling in patients with reduced left ventricular ejection fraction (LVEF), however, their role in patients with aortic stenosis after transcatheter aortic valve replacement (TAVR) is unknown. In this retrospective cohort study, 21,312 patients older than 65 years who underwent TAVR between July 2014 and January 2016 were analyzed, 8,468 of whom were prescribed a RAS inhibitor at the time of hospital discharge (RAS inhibitor group). The RAS inhibitor and non-RAS inhibitor groups were then compared to determine all-cause mortality within 1 year after hospital discharge and readmission due to heart failure within 1 year after discharge. After propensity matching, a total of 15,896 patients with similar propensity scores for prescription of a RAS inhibitor were included. At baseline, patients in the RAS inhibitor group had a lower LVEF, were more likely to be prescribed a concomitant beta-blocker, and were more likely to have atherosclerotic comorbidities as compared with the non-RAS inhibitor group. Researchers found that the mortality rate after 1 year was significantly lower in the RAS inhibitor group than in the non-RAS inhibitor group (HR 0.82, 95% CI 0.76 to 0.90). Moreover, the rate of readmission for heart failure was significantly lower in the RAS inhibitor group than in the non-RAS group (HR 0.86, 95% CI 0.79 to 0.95). Of note, a significant interaction between having a RAS inhibitor prescription and LVEF was identified (p=0.04); as such the data was stratified by LVEF. For patients with preserved LVEF, patients in the RAS inhibitor group had a lower 1-year mortality rate than those in the non-RAS inhibitor group (HR 0.78, 95% CI 0.71 to 0.86). These findings were not observed amongst patients with reduced LVEF (HR 0.95, 95% CI 0.81 to 1.12). The main limitation of this study was the potential selection bias. Overall, results from this study indicate that prescribing a RAS inhibitor after TAVR may reduce overall mortality and hospital readmissions, however, randomized trials are needed to validate this result.
While obesity has been shown to increase the risk of developing gestational diabetes mellitus (GDM) and preeclampsia (PE) in pregnancy, the association between metabolic syndrome and adverse pregnancy outcomes has not been investigated. In this multicenter prospective cohort study, 5,530 nulliparous women with singleton pregnancies recruited between November 2004 and February 2011 were followed up to assess the association between metabolic syndrome (MetS) and pregnancy outcomes. MetS was defined using the International Diabetes Federation (IDF) MetS criteria, assessed at 15  1 weeks’ gestation. Variables included in the IDF MetS criteria include increased waist circumference, increased triglycerides, reduced high density-lipoprotein C (HDL-C), increased blood pressure, and increased fasting blood glucose. Pregnancy outcomes included preeclampsia, gestational diabetes mellitus (GDM), spontaneous preterm birth (sPTB), large for gestational age (LGA) and small for gestational age (SGA). Researchers found that 12.3% of women had MetS.  Women with MetS had an increased risk of preeclampsia by a factor of 1.63 (95% CI 1.23 to 2.15) and GDM by a factor of 3.71 (95% CI 2.42 to 5.67). A diagnosis of MetS was not associated with an increased risk of sPTB, LGA, or SGA. It should be noted that this study has limited generalizability as 90% of study participants were white. This study also did not compare the impact of individual metabolic components to that impact of MetS on pregnancy outcomes. Overall, results from this study indicate that women with metabolic syndrome are more likely to develop preeclampsia and GDM compared to women without MetS.
The selective serotonin reuptake inhibitor (SSRI) fluoxetine is commonly used in treating depression and emotional lability after stroke. Results from previous small trials have also suggested that fluoxetine may have a role in improving functional outcomes after stroke, although this potential effect has not been studied in a large controlled trial. In this randomized controlled trial, 3,127 patients with a clinical diagnosis of acute stroke were assigned to either 20 mg fluoxetine or placebo once daily for 6 months to study the impact on functional status as assessed by the modified Rankin Scale (mRS). Researchers found that functional status was similar between the two groups at 6 months (common OR 0.951, 95% CI 0.839 to 1.079, p=0.439). Patients in the fluoxetine group were less likely to be diagnosed with new depression at 6 months (13.43%) than those in the placebo group (17.21%) (difference 3.78%, 95% CI 1.26 to 6.30, p=0.0033). However, patients in the fluoxetine group were also at an increased risk of bone fracture at 6 months (2.88%) as compared to those in the placebo group (1.47%) (difference 1.41%, 95% CI 0.38 to 2.43, p=0.0070). The primary limitation of this trial was that there was only moderate adherence to the trial medication, which may have resulted in underestimation of the treatment effect. In summary, results from this trial do not support this use of fluoxetine for recovery of function after acute stroke.
Umbilical cord blood (UCB) is a rich source of stem cells for transplantation in patients with hematologic malignancies. However, its widespread utilization has been limited by the generally slow rate of hematopoietic recovery. In a first-in-human pilot study of an ex-vivo expanded UCB product (NiCord) used in combination with nicotinamide to expand repopulating hematopoietic stem cells, stable NiCord-derived hematopoiesis was observed for more than 7 years. In this multicenter phase I/II single-arm study, 36 patients with high-risk hematologic malignancies and no readily available matched adult donor were transplanted with a single, expanded UCB graft (NiCord) after myeloablative conditioning. The primary outcomes were the incidence of neutrophil engraftment at 42 days and the incidence of secondary graft failure. Results were compared to data from a matched cohort of 146 patients who underwent UCB transplantation between 2010 and 2013 from the Center for International Blood and Marrow Transplant Research (CIBMTR). Researchers found that the age-adjusted cumulative incidence of neutrophil engraftment at 42 days after transplantation was higher in the NiCord recipients (94%) than in the CIBTMR comparator cohort (85%) (p<0.001). One NiCord recipient experienced primary graft failure, and two patients experienced secondary graft failure. The cumulative incidence of grade 2 to 4 graft-versus-host disease (GVHD) at day 100 was 44% in the NiCord recipients (95% CI 28% to 60%), and the cumulative incidence of chronic GVHD at 3 years was 40% (95% CI 24% to 57%). Overall, this study suggests that use of a stand-alone ex-vivo expanded UCB graft may be efficacious and safe. An ongoing phase III trial comparing NiCord to standard myeloablative UCB transplantation will provide conclusive results.
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