2 Minute Medicine Rewind December 9, 2020

Risk of mortality associated with concomitant antidepressant and benzodiazepine therapy among patients with depression: a population-based cohort study

1. Concomitant antidepressant and benzodiazepine therapy was associated with an increased risk of all-cause mortality over antidepressant monotherapy in patients with depression.

Evidence Rating Level: 2 (Good)

As antidepressants (ADs) may take several weeks to show therapeutic effect, benzodiazepines (BZDs) are often prescribed concomitantly to manage anxiety or insomnia in patients with depression starting on these medications. However, patients often continue taking benzodiazepines beyond this initial period, with one study finding approximately 12% of patients who received AD+BZD concomitantly, continuing BZDs long-term. There is limited real world data on the efficacy and safety outcomes associated with long-term concomitant BZD+AD use. This population-based cohort study classified 612 729 patients with incident depression, who filled prescriptions from 2002 to 2017 within 6 months of diagnosis according to South Korea’s nationwide healthcare database, into two groups: patients who were taking AD+BZD therapy and those on AD monotherapy. These groups were matched in a 1:1 ratio to balance baseline characteristics; however, while subgroup analyses were performed based on age and sex, their model did not include the history of other anxiolytic use as a confounding variable. Compared to AD monotherapy, AD+BZD therapy was associated with an increased risk of all-cause mortality (adjusted HR 1.04, 95% CI 1.02-1.06) and all-cause hospitalization (adjusted HR 1.05, 95% CI 1.04-1.06). This effect was increased among males (adjusted HR 1.11, 95% CI 1.08-1.15) and those younger than 65 years old (adjusted HR 1.33, 95% CI 1.29-1.38), while the opposite effect, a reduction in all-cause mortality, was seen in females and patients over 65 years old. This increased risk of mortality was also similar between patients who discontinued BZDs and those who continued BZDs. Finally, a 74% increased risk of suicide attempts and self-harm were seen in the AD+BZD group. These results suggest that prescribers should weigh the risks against the benefits when prescribing concomitant AD+BZD therapy for depression. Further studies would be needed to fully describe how age, gender, or other underlying factors responsible, may impact this associated risk with all-cause mortality.


The efficacy and safety of methylprednisolone in hepatitis B virus-related acute-on-chronic liver failure: a prospective multi-center clinical trial

1. Adding methylprednisolone to standard treatment in hepatitis B virus-related acute-on-chronic liver failure was associated with an increase in 6-month survival rate.

Evidence Rating Level: 1 (Excellent)

Hepatitis B virus-related acute-on-chronic liver failure (HVB-ACLF), accounting for 70% of all ACLF cases in Asia, is a severe exacerbation of liver function leading to high mortality rates. WIth liver transplantation as the only curative treatment, there is a lack of efficacious treatment options for these patients. As systemic inflammation secondary to a cytokine storm is a key feature of ACLF, methylprednisolone (MP) has been theorized to play a role in its treatment; particularly when combined with nucleoside analogs (NAs), this combination may reverse potential HBV-related liver deterioration. However, the use of MP in HBV-ACLF remains uncertain and controversial. In this multicentre, prospective randomized controlled clinical trial, 171 patients (mean age 45.2 years, 88.9% men) with HBV-ACLF were recruited from three medical centres in Beijing. They were randomized in a 1:1 ratio to receive either MP (1.5mg/kg/day IV for 3 days, 1mg/kg/day IV for 2 days, then 0.5mg/kg/day IV for 2 days) plus standard treatment or standard treatment only (the control group). At 6 months, the mortality rate of the MP group was lower than the control group (32.4% vs 42.5%, p=0.0037), while there was no significant difference in liver transplants between the groups. The univariate analysis and collinearity diagnosis showed that MP was an independent predictor for mortality among HBV-ACLF patients (HR 0.547, p=0.040). Cox analysis identified HBV DNA and lymphocyte/monocyte ratios (LMRs) as predictors of mortality, in the MP group. In terms of adverse events, incidence of hypoalbuminemia (56.6% vs 37.5%, p=0.012), fungal infection, ascites, hepatic encephalopathy, and new onset infection (41.1% vs 31.8%, p=0.214) were higher in the MP group. While the timing of MP administration plays a major role in treatment efficacy, most patients were transferred to the medical centres after spending a median of 16 days and 20 days in primary care, in the MP and control groups respectively. As this study could not determine the significance of MP onset time, future studies should explore this factor when evaluating the potential efficacy of MP therapy in HBV-ACLF.


Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study

1. There is a U-shaped association of LDL-C levels and risk of all-cause mortality with the lowest risk at LDL-C levels of 3.6 and 2.3 mmol/L in patients not on or on lipid lowering therapy, respectively.

2. There is a similar U-shaped association of LDL-C levels and risk of mortality due to cancer causes and other causes but not cardiovascular causes.

Evidence Rating Level: 2 (Good)

Low density lipoprotein cholesterol (LDL-C) is a well-known causal risk factor for cardiovascular disease and cardiovascular events. However, LDL-C’s association with all mortality is not as clear, with studies showing no association and, at times, inverse association. In this prospective cohort study, 108 243 participants from the Copenhagen General Population Study from the national Danish Civil Registration System were followed for a median of 9.4 years and data for all-cause mortality, cause specific mortality and LDL-C levels were extracted. The risk of all-cause mortality was U-shaped and compared to patients with LDL-C of 3.4-3.9 mmol/L. Multivariable analysis showed increased risk of mortality for individuals with LDL-C less than 1.25 mmol/L (aHR 1.25, 95%CI 1.15-1.36) and greater than 4.8 mmol/L (aHR 1.15, 95%CI 1.05-1.27). The LDL-C level associated with the lowest risk of all-cause mortality was 3.6 mmol/L in patients not receiving lipid lowering therapy and 2.3 mmol/L in patients receiving lipid lowering therapy. This association also existed for cancer mortality and other mortality but not for cardiovascular mortality where no association was found (though risk of fatal MI increased with increased LDL-C). These results can help healthcare professionals better define healthy LDL-C levels and guide guidelines on targets for the general population. Limitations of this study include a homogenous population in a single country, certain confounders could not be adjusted for, such as patients who discontinue or begin lipid-lowering therapy during follow-up or the impact of non-pharmacological interventions such as weight loss, and it is observational by design and cannot be used to infer causality.


A randomized trial of strategies using Darbepoetin Alfa to avoid transfusions in CKD

1. In patients with CKD, fixed low dose of erythropoietin provides similar efficacy outcomes, such as percentage of patients requiring transfusions, as titration-based dosing based on Hgb levels while decreasing cumulative dose of erythropoietin needed.

Evidence Rating Level: 1 (Excellent)

Chronic kidney disease (CKD) patients have parenchymal loss leading to decreased erythropoietin production and anemia. Historically, anemia due to CKD often required erythropoietin-stimulating agents (ESAs) to increase their hemoglobin (Hgb) and ESAs were titrated to reach certain Hgb levels. ESA exposure can lead to increased cardiovascular events and thus alternative dosing strategies to maximize efficacy (decreased need for transfusions) and safety (decreased cardiovascular events) are needed.  In this multicenter, pharmaceutical-sponsored (part of FDA postmarketing requirement), phase 3 randomized controlled trial, 756 patients with non-dialysis CKD were randomized into a 1:1 ratio of receiving either darbepoetin every 4 weeks based on titration Hgb to ≥ 10.0 g/dL (with dose reduction if rapid rate of rise or Hgb ≥ 10.5 g/dL) or darbepoetin fixed dose of 0.45 µg/kg every 4 weeks (with pausing of treatment if Hgb >12.0 g/dL or if systolic BP ≥ 160 mmHg for two consecutive visits). Patients were stratified by RBC transfusions received in the past year and site practice setting. There was no significant difference between the percentage of patients needing transfusions between the titration dose group or fixed dose group (24.4% vs. 24.1%) with similar time to first transfusion. The titration dose group had significantly higher median hemoglobin levels compared to fixed dose group (9.9 g/dL vs 9.4 g/dL) and higher median monthly dose of darbepoetin (53.6 ug vs. 30.9 ug, respectively). Though there were trends of better safety outcomes in the fixed dose group, there was no significant difference in endpoints such as all-cause mortality (HR 0.96), CV mortality (HR 0.89), stroke (HR 4.79), MI (0.75), decompensated HF (HR 0.70), TE events (HR 0.49) and combinations of these. These findings suggest that low fixed dose of ESAs may be a viable alternative to a titration-based strategy for minimizing transfusions and decreasing cumulative dose of ESAs. Limitations in this study include withdrawal of a significant number of patients (756 subjects enrolled, 458 completed the study) but there was equal withdrawal from both groups with similar percentages for each reason. The number one reason was due to developing end-stage renal disease requiring renal replacement therapy (90 subjects from each group). Future studies should be powered for safety endpoints to show improved safety outcomes in addition to non-inferiority efficacy outcomes for low fixed dose of ESAs.


Preoperative levels of natriuretic peptides and the incidence of postoperative atrial fibrillation after noncardiac surgery: a prospective cohort study

Evidence Rating Level: 2 (Good)

1. Preoperative levels of brain-type natriuretic peptide were independently associated with postoperative atrial fibrillation after noncardiac surgery.

Postoperative atrial fibrillation (POAF) after noncardiac surgery has been associated with prolonged hospital stays and an increased risk of stroke and death. As an established marker in heart failure management and diagnosis, levels of brain-type natriuretic peptide (BNP) are used to predict cardiovascular morbidity and mortality, including new onset AF. However, its ability to predict POAF after non-cardiac surgery remains unknown. From VISION (Vascular events In non-cardiac Surgery patients cOhort evaluatioN), a prospective international cohort study, 37 760 patients were included in the analysis. Patients were phoned to gather data on whether they experienced clinically important POAF within the 30 days following their procedure, while blood samples were collected from 9 789 patients (26%) to measure pre-operative N-terminal pro-BNP levels. Results showed that the incidence of clinically important POAF following noncardiac surgery was 1.0% (95% CI 0.9-1.1), which was at its highest after major thoracic surgery (3.2%, 95% CI 2.3-4.4). Using logistic regression models and an NT-proBNP level of 100 ng/L as a reference value, increasing preoperative NT-proBNP levels of 200, 1500, and 300 ng/L were associated with adjusted ORs for POAF of 1.31 (95% CI 1.15-1.49), 2.07 (95% CI 1.27-3.36), and 2.39 (95% CI 1.26-4.51) respectively. Compared to other potential predictors in their model, NT-proBNP provided 16% more information over other prognostic factors. However, shorter, mostly asymptomatic episodes of POAF were likely not captured through their survey methods, as no extended holter monitoring was used. Given this predictive value of NT-proBNP in POAF, further studies should explore whether there is an underlying causal relationship with different cardiovascular diseases, which may lead to cardiac stress elevating these BNP levels.

Image: PD

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