2 Minute Medicine Rewind December 21, 2015
Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Lack of reversibility is a major consideration when using the new Factor Xa inhibitors (apixaban and rivaroxaban) for stroke prevention in atrial fibrillation. The drug Andexanet has been designed to reverse the anticoagulant effects with modified decoy Factor Xa proteins that catalytically inactive Factor Xa inhibitors. A two-part randomized placebo-controlled study was conducted to evaluate the reversibly of Andexanet compared to placebo and to compare its efficacy as a bolus or as a bolus plus 2-hour infusion. The primary outcomes of the study were the mean percent change in anti-factor Xa activity. The authors found that in patients given apixaban, anti Xa activity was reduced by 94% when given a Andexanet bolus compared to 21% in those given placebo (p<0.001). Thrombin generation was fully restored in 100% of patients given Andexanet vs 11% in patients given placebo within 2-5 minutes. Comparably, in patients given rivaroxaban, anti-factor Xa activity was reduced by 92% in those given an Andexanet bolus compared to 28% in placebo (p<0.001). Thrombin generation was fully restored in 96% vs 7% of patients on placebo. Comparing bolus to bolus plus infusion, the effects were sustained. There were no serious events or thrombotic events in the trial. Overall, Andexanet was able to effectively reverse the anticoagulant activity of apixaban and rivaroxaban within minutes without any major adverse events. The ability to reverse factor Xa inhibitors will result in there even greater use in the near future.
Currently the standard of care for CNS glioblastoma is maximal safe surgical resection followed by radiotherapy and chemotherapy (i.e. temozolomide). Despite this multimodal therapy, glioblastoma has a very poor prognosis as median mortality is typically within 1-2 years after diagnosis. The purpose of this multicenter randomized trial from 2009 to 2014 was to evaluate the effectiveness and safety of tumor-treating fields (TTFields) used in conjunction with chemotherapy as maintenance treatment. Patients were randomized to receive with TTFields plus chemotherapy with remozolomide for 5 days of each 28-day cycle (n=466), or temozolomide alone (n=229). TTFields are delivered continuously through four transducer arrays on the scalp. The primary end point was progression-free survival and the secondary end point was overall survival. The authors found the primary end point of median progression-free survival was 7.1 months in the TTFields plus temozolomide group and 4.0 months in the temozolomide alone group (HR 0.62 [98.7% CI, 0.43-0.89]; p = .001). For the secondary end point, median overall survival was 20.5 months in the TTFields plus temozolomide group and 15.6 months in the temozolomide alone group (HR, 0.64 [99.4% CI, 0.42-0.98]; p = .004). Therefore, the addition of TTFields to the maintenance treatment with temozolomide significantly prolonged both progression-free and overall survival in this patient population.
Predictors for atrial fibrillation detection after cryptogenic stroke
Paroxysmal atrial fibrillation, diagnosed using longer duration loop monitors, has been found in a significant proportion of patients with stroke of previously unknown cause or cryptogenic stroke. The main objective of this study was to assess presence of atrial fibrillation as the cause of cryptogenic stroke within the initial 12 and 36 months of follow up using insertable cardiac monitors. Variables that were assessed to be predictors included age, sex, race, body mass index, type and severity of index ischemic stroke, CHADS2 score, PR interval, premature atrial contractions and presence of certain comorbid risk factors (diabetes, hypertension, congestive heart failure, or patent foramen ovale). The authors detected atrial fibrillation in 29 (of 221) patients within 12 months and 42 patients at 36 months. Significant univariate predictors of atrial fibrillation at 12 months were: premature atrial contractions (HR 3.9 for >123 vs 0; [confidence interval 1.3-12.0], p = 0.009 across quartiles), diabetes (HR 2.3 [1.0-5.2], p < 0.05), age (hazard ratio [HR] per decade 2.0 [1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), and PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001). In the multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant. Independently, age and prolonged PR interval were significantly related, however only moderately predictive, in incidence of atrial fibrillation in cryptogenic stroke.
A subset of patients with Crohn’s disease do not respond or gradually lose response to medical treatment and are not amenable to surgery. In these patients a hematopoietic stem cell transplantation (HSCT) may have a role. The purpose of this randomized clinical trial in eleven European transplant units from 2007 to 2011 was to evaluate the effectiveness of HSCT in refractory Crohn’s disease. Patients were randomized to immunoblation and HSCT (n=23) or control treatment (HSCT deferred for 1 year). The primary outcomes was sustained disease remission at 1 year which was defined as clinical remission, no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active disease anywhere in the gastrointestinal tract. The authors found no statistically significance between the two groups in proportions of patients achieving sustained disease remission and a statistically significant difference among patients able to discontinue active treatment in last 3 months. In terms of adverse events, more events occurred in patients who underwent HSCT. Overall, there was no difference in improvement in sustained disease remission at 1 year and HSCT was associated with significant toxicity.
Effect of Availability of Transcatheter Aortic-Valve Replacement on Clinical Practice
Transcatheter aortic-valve replacement (TAVR) has been recently established as an effective option for patients in which surgery, the gold standard treatment, is considered high-risk. The purpose of this study was to evaluate the frequency and effectiveness of these two options and how they have evolved in Germany over the years from 2007 to 2013. Over this time period, there was a total of 88,573 admissions to the German hospitals for either procedure. The number of TAVR procedures increased from 144 to 9147, compared to the number of surgeries which decreased from 8622 to 7048. For surgeries, there was a decline in the use of mechanical prostheses and the use of bioprosthetic implants remained almost unchanged. In terms of patient characteristics, older individuals (mean [±SD] age, 81.0±6.1 years vs. 70.2±10.0 years) and those at higher preoperative risk were selected for TAVR. Mortality decreased for both options. Specifically, it decreased from 13.2% to 5.4% with TAVR compared to 3.8% to 2.2% with surgery. Over the years the rate of adverse events such as stroke, bleeding, and pacemaker implantation (but not acute kidney injury) decreased. Overall, the incidence of TAVR increased significantly over the years with moderate reduction in surgery frequency, and mortality deceased in both groups but to a greater extent for TAVR procedures.
Image: PD
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