2 Minute Medicine Rewind September 14 – 20, 2015
For patients with advanced or recurrent prostate cancer, androgen deprivation is the standard frontline therapy. However, this approach causes a number of adverse effects, including fatigue, sexual dysfunction and changes to cognition. In addition, despite initial response rates of up to 90%, nearly all men ultimately develop castration-resistant disease. As a means of prolonging the duration of response and preserving quality of life, intermittent androgen deprivation has been studied as an alternative to continuous therapy. While there have been several studies investigating the efficacy and safety of intermittent androgen deprivation, its use continues to be controversial and guidelines are variable. In this systematic review and meta-analysis, the results of 15 randomized clinical trials were extracted and included in a quantitative synthesis to study efficacy and tolerability of intermittent versus continuous androgen deprivation therapy in the treatment of prostate cancer. Primary outcomes were overall survival and quality of life. Among the studies included in the review, almost all had variable off-treatment periods, with the exception of one in which a 6-month interval was used, and another in which duration was not stated. The authors found that there was no difference in overall survival between intermittent and continuous therapy (5352 patients, HR 1.02, 95% CI 0.91-1.11). Due to considerable heterogeneity across studies with respect to the tools used to assess patient quality of life, a meta-analysis could not be performed for this outcome. However, 2 trials reported a better overall quality of life with intermittent therapy, and 3 trials did not observe any difference between the 2 therapeutic approaches. Another 7 trials observed an increase in quality of life with intermittent therapy but only in certain domains, such as physical and sexual functioning. Three of the 7 trials also noted an improvement in quality of life in the continuous therapy group, however. Additional meta-analyses revealed no significant difference between treatment groups for cancer-specific survival (3613 patients, HR 1.02, 95% CI 0.87-1.19), disease progression (3523 patients, HR 0.96, 95% CI 0.76-1.21) or progression-free survival (1774 patients, HR 0.94, 95% CI 0.84-1.05). With respect to time to castration resistance, 2 of the 4 trials evaluating this outcome observed a statistically significant difference in favor of intermittent therapy, however insufficient data was available to perform a pooled analysis. For adverse events, of which 12 trials provided data on this outcome, there was no significant difference between groups for all reported adverse effects; pooled estimates, however, favored intermittent androgen deprivation. This study therefore shows that intermittent androgen deprivation is not inferior to continuous therapy in terms of overall survival and other patient-related outcomes. It should be noted, however, that in assessing risk of bias, all but one trial were of unclear or high risk.
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Individuals with type 2 diabetes are at an increased of developing cardiovascular disease, and the co-existence of these diseases increases one’s risk of death. While some evidence indicates that glucose lowering may reduce the incidence of cardiovascular events and death in patients with type 2 diabetes, there is concern that intensive glucose lowering and/or the use of specific glucose-lowering pharmaceuticals may be linked to adverse cardiovascular outcomes. Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which reduces hyperglycemia by decreasing renal glucose reabsorption, and therefore increasing urinary excretion of glucose. In part a result of the drug’s mechanism of action, the most common side effects of empagliflozin are urinary tract and genital infection. In this randomized controlled trial, 7020 adults with type 2 diabetes and established cardiovascular disease were randomized to receive either 10 mg of empagliflozin, 25 mg of empagliflozin or placebo once daily, to examine the effects of empagliflozin on cardiovascular and mortality in patients with type 2 diabetes at high risk of experiencing a cardiovascular event. The median duration of treatment was 2.6 years. Researchers found that the primary outcome (death due to cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke) occurred less frequently among patients in the pooled empagliflozin group (10.5%) compared to the placebo group (12.1%) (HR 0.86, 95.02% CI 0.74-0.99). In analyzing outcomes separately, the researchers found that compared to placebo, empagliflozin resulted in a significantly lower risk of death from cardiovascular causes (HR 0.62, 95% CI 0.49-0.77), death from any cause (HR 0.68, 95% CI 0.57-0.82), and hospitalization for heart failure (HR 0.65, 95% CI 0.50-0.85). There were no significant between-group differences in the occurrence of myocardial infarction of stroke. With respect to glycemic control, after 12 weeks, the adjusted mean difference in glycated hemoglobin levels between patients receiving empagliflozin and those receiving placebo were -0.54 percentage points (95% CI -0.58 to -0.49) in the 10 mg group and -0.60 percentage points (95% CI -0.64 to -0.55) in the 25 mg group. In addition, compared to placebo, the use of empagliflozin over the course of the study was associated with small reductions in weight, waist circumference, uric acid level and blood pressure with no increase in heart rate, and small increases in LDL and HDL cholesterol. This study therefore shows that patients with type 2 diabetes may lower their risk of experiencing a cardiovascular event through the use of empagliflozin when compared to placebo.
Paroxetine has been used in the treatment of depression in adolescents. Its use has been largely supported by the results of Study 329, funded by pharmaceutical company GlaxoSmithKline (GSK), which concluded that the drug was both safe and effective in this patient population. The “restoring invisible and abandoned trials” (RIAT) initiative, however, identified Study 329 as an example of a misreported trial in need of restoration, particularly in light of the study’s influence in supporting the use of antidepressants in adolescents. In the original multicenter randomized controlled trial, 275 adolescents aged 12-18 years who met DSM-IV criteria for major depression were randomized to receive paroxetine, imipramine or placebo to examine the efficacy and safety of imipramine and paroxetine in treating adolescents with unipolar major depression. The pre-specified primary efficacy variables were changed from baseline to the end of the 8 weeks in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score =<8 or >=50% reduction in baseline HAM-D) at acute endpoint. In reanalyzing the original dataset from this study, the current authors found no statistical or clinical significant changes in HAM-D scores from baseline. HAM-D scores decreased by 10.7 (least squares mean) (95% CI 9.1-12.3), 9.0 (95% CI 7.4-10.5), and 9.1 (95% CI 7.5-10.7) points, respectively, for patients in the paroxetine, imipramine and placebo groups (p = 0.20). In reviewing case reports, the authors also found that adverse events were not consistently transcribed into patient-level listings of adverse events. While some but not all gastrointestinal, respiratory, and other adverse events were reported, psychiatric events for paroxetine and placebo groups, and cardiovascular events in the imipramine group were omitted in the original publication. This study therefore shows that neither paroxetine or imipramine demonstrate efficacy in the treatment of major depression in adolescents, and in fact, have potential to cause patient harm.
Patients with congenital heart disease (CHD) are faced with ongoing morbidity and reduced long-term survival. Due to ongoing improvement in care, survival has increased in patients with CHD and mortality has shifted away from infants and towards adults. In this retrospective cohort study, 6969 patients age 16 years and older were followed-up and compared to an age and gender-matched population, to assess survival prospects and causes of death, and establish mortality rates for patients with adult CHD. The mean age at baseline was 29.9 years, and 69%, 26% and 5% of patients were in New York Heart Association (NYHA) functional classes I, II, and III/IV, respectively. According to the Bethesda disease complexity classification, 52% of patients had simple defects, 33% moderate, and 15% had great complexity defects. Researchers found that over the course of a median follow-up of 9.1 years, 524 patients (7.7%) died, producing a mortality rate of 0.72%/patient-year. Most patients died outside of hospital (81.9%), and leading causes of death were chronic cardiac failure (42.5%), pneumonia (10.2%) and sudden cardiac death (7.0%). Cardiac surgery and/or cardiac intervention accounted for only 4.8% of deaths in the entire cohort. Compared to the expected mortality from an age and gender-matched general population, the mortality rate for the entire cohort was significantly higher (standardized mortality ratio (SMR) 2.29, 95% CI 2.08-2.53). In analyzing specific subgroups, the SMR was found to be highest in patients with Fontan circulation (SMR 2.40, 95% CI 15.97-34.29), complex CHD (SMR 14.13, 95% CI 10.71-18.64), and Eisenmenger syndrome (SMR 12.79, 95% CI 9.67-16.91). No significant difference in mortality was seen in patients with ductus arteriosus, atrial or ventricular septal defects, when compared to the general population. This study therefore shows that adults with CHD continue to be at an increased risk of mortality compared to the general population, with certain patient subgroups (i.e. Fontan physiology, Eisenmenger syndrome) at particularly elevated risk.
Tamoxifen and third-generation aromatase inhibitors (i.e. anastrozole, exemestane, letrozole) are standard therapies in the treatment of estrogen receptor (ER) positive advanced breast cancer in postmenopausal women. However, in light of the high prevalence of resistance to aromatase inhibitors, it is important that other treatment options with unique mechanisms of action be explored. This includes fulvestrant, a selective estrogen receptor (ER) antagonist that suppresses estrogen signaling. In this multicenter randomized controlled trial, 205 postmenopausal women with ER positive, locally advanced or metastatic breast cancer that had not previously received therapy for advanced disease were randomized to receive either 500 mg of fulvestrant (days 0, 14, 28 and every 28 days thereafter) or 1 mg anastrozole daily, to compare overall survival. Overall survival was assessed after approximately 65% of the study population had died. At this time, researchers found that 61.8% of patients in the fulvestrant group had died, compared to 71.8% in the anastrozole group (HR 0.70, 95% CI 0.50-0.98). This was a post-hoc analysis of overall survival and was not pre-specified, however this study suggests that fulvestrant may extend overall survival compared to anastrozole.
Image: PD
©2015 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.
![Adverse pregnancy outcomes associated with thrombophilias [Classics Series]](https://www.2minutemedicine.com/wp-content/uploads/2015/07/Classics-2-Minute-Medicine-e1436017941513-75x75.png)
