2 Minute Medicine Rewind January 16, 2017
Trial of amitriptyline, topiramate, and placebo for pediatric migraine
The management of migraine headaches in the pediatric population has always been a challenge, given the lack of rigorous evidence for specific therapies. This was a multicenter, phase 3, randomized control trial held over 24 weeks that aimed to study two commonly used medications for migraine prevention, amitriptyline and topiramate. 361 patients aged 8 to 17 who suffered from a migraine of at least four days per month were randomized in a 2:2:1 ratio to receive amitriptyline, topiramate, or placebo. The study was ended early due to futility. Researchers found no significant difference between groups for a reduction of 50% or more in headache days compared with baseline, the primary outcome. This occurred in 52% of amitriptyline patients (p = 0.26 vs. placebo), 55% of topiramate patients (p = 0.48 vs. placebo and p = 0.49 vs. amitriptyline), and 61% of placebo patients. There was also no difference for headache-related disability or headache days. A greater number of amitriptyline patients experienced fatigue (30% vs. 14% of placebo) and dry mouth (25% vs. 12%), and a greater number of topiramate patients experienced paresthesia (31% vs. 8% of placebo) and weight loss (8% vs. 0%). In conclusion, amitriptyline and topiramate were associated with higher rates of adverse events and provided no difference in migraine frequency reduction compared to placebo.
Relation between resting amygdalar activity and cardiovascular events
Previous research has shown an association between activity in the amygdala, a brain region involved in stress, and post-traumatic stress disorder, anxiety, and depression. However, no studies have identified such a link with stress-related cardiovascular events. In this longitudinal cohort study, researchers followed 293 individuals aged 30 or older with no known cardiovascular disorders who underwent combined PET/CT imaging at an academic hospital in Boston between January 2005 and December 2008 to assess amygdalar activity, bone marrow activity, arterial inflammation, and risk for cardiovascular events, event, including heart attack, angina, heart failure, stroke, and peripheral arterial disease. They were tracked for an average of 3.7 years, during which 22 patients had a cardiovascular event. Amygdalar activity was associated with increased bone marrow activity (r = 0.47, p < 0.0001), arterial inflammation (4 = 0.49, p < 0.0001), and risk for cardiovascular disease events (HR 1.59, 95% CI: 1.27 to 1.98). Significance remained robust after multivariate adjustments. Investigators conclude that amygdalar activity independently predicted cardiovascular disease events, possibly due to a mechanism whereby the amygdala signals to the bone marrow to increase leukocyte production, which then causes increased arterial inflammation, heart attack, and stroke.
Secondary hyperparathyroidism can lead to bone and cardiovascular disorders, neuropathy, myopathy, among other deadly complications. Etelcalcetide is an intravenous, second generation calcimimetic that has been recently approved in Europe and is under review by the FDA. These were two parallel, phase 3, randomized control trials conducted in the U.S., Canada, Europe, Israel, Russia, and Australia involving 1023 patients who were receiving hemodialysis with moderate to severe secondary hyperparathyroidism. The first trial had 508 patients from March 2013 to June 2014; the second had 515 patients from March 2013 to May 2014. Patients were randomized in a 1:1 ratio to receive IV etelcalcetide or placebo after each hemodialysis session for 26 weeks. Significantly more etelcalcetide patients reached the primary outcome of a 30% or more reduction in serum PTH during weeks 20-27 from baseline compared to placebo (74.0% vs. 8.3%, respectively, p < 0.001 for trial A; 75.3% vs. 9.6%, p < 0.001 for trial B). Similarly, etelcalcetide patients were more likely to achieve a mean PTH of 300 pg/mL or lower (49.6% vs. 5.1% placebo, p < 0.001 for trial A; 53.3% vs. 4.6%, p < 0.001 for trial B). Etelcalcetide patients experienced more muscle spasms, nausea, and vomiting. Therefore, use of etelcalcetide shows initial promise for patients receiving hemodialysis with secondary hyperparathyroidism, yet more studies are warranted to evaluate long-term effects.
Tranexamic acid in patients undergoing coronary-artery surgery
Tranexamic acid is often used to prevent excessive blood loss for patients undergoing coronary-artery surgery, however little is known about its benefits after surgery. In this randomized, placebo-controlled trial, 4631 patients scheduled for coronary-artery surgery were randomized in a 2-by-2 factorial design to receive a combination of aspirin or placebo and tranexamic acid or placebo. The primary outcome was death or thrombotic complications, including myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction, within 30 days post-surgery. There was no significant difference in primary outcome between groups (16.7% of tranexamic acid patients and 18.1% of placebo patients, relative risk 0.92, 95% CI: 0.81 to 1.05, p = 0.22). Patients receiving tranexamic acid did have a significantly lower number of transfused blood product units during hospitalization (4331 vs. 7994 for placebo, p < 0.001) as well as decreased incidences of major hemorrhage or cardiac tamponade leading to reoperation (1.4% vs. 2.8% of placebo, p = 0.001). As suspected from prior studies, tranexamic acid was associated with a higher risk of postoperative seizures (p = 0.002). In conclusion, tranexamic acid reduces blood loss without significantly improving or worsening mortality or thrombotic complications within a month after cardiac surgery.
Prolonged versus standard specialized early intervention treatment for first episode psychosis
Specialized early intervention (SEI) has been crucial to the treatment of psychosis and encompasses assertive community treatment, social skills training, and family involvement. In Denmark, standard of care for first episode schizophrenia is currently two years of SEI followed by three years of standard treatment in community health centers. The purpose of this study was to test whether the positive effects would be extended if patients received prolonged five-year SEI. In this randomized parallel group trial, 400 Danish patients with schizophrenia spectrum disorder who were 19 months into a two-year SEI program were randomized to continue SEI for three additional years or discontinue after the standard two years. The primary end point was reduction of negative symptoms, as determined by follow-up interview and the scale for assessment of negative symptoms (avolition-apathy, anhedonia, alogia, affective blunting). Investigators identified no significant difference for levels of negative symptoms (1.72 for the prolonged group vs. 1.81 for the control group, p = 0.39, 95% CI: 0.33 to 0.13). Prolonged SEI patients were more likely to keep in contact with specialized mental health services and had higher client satisfaction (p < 0.001). This study reveals that prolonged SEI for first episode psychosis yielded few clinical effects, and treatment should continue to target the early, more unstable stages of illness.
Image: PD
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