Chiefs’ Inquiry Corner – 10/5/2022

The traditional paradigm for management of atrial fibrillation (AF) typically favors rate control strategies over rhythm control, though rhythm control strategies can subsequently be used for symptom relief or for improvement in quality of life. By restoring sinus rhythm, the increased risk for mortality and morbidity from stroke and congestive heart failure can potentially be ameliorated. In 2020, the EAST-AFNET-4 trial demonstrated that early rhythm control (within 12 months of AF diagnosis) in high risk patients improved cardiovascular outcomes. More recently, a follow-up retrospective study of > 54,000 Korean patients again showed that early rhythm control (98% with antiarrhythmic drugs, rather than ablation) was associated with significantly lower incidences of a composite outcome that included cardiovascular death, ischemic stroke, acute myocardial infarction, and heart failure hospitalization. Each individual component of the composite outcome was shown to have a statistically significant decrease; there was also a statistically significant decrease in all-cause mortality. This benefit was shown in populations that were both high risk (median age 70, median CHA2DS2-VASc score 4) and lower risk (median age 54, median  CHA2DS2-VASc score 1), perhaps indicating a need to shift to away from traditional management paradigms.

References: Early Rhythm Control

For patients with diabetic neuropathy, guidelines recommend initial treatment with amitriptyline, duloxetine, pregabalin, or gabapentin. However, patients can often have symptoms that are refractory to monotherapy. Clinicians may choose to add a second medication as adjunctive therapy, but this strategy has not been assessed in high-quality studies. A recent study in the Lancet compared three treatment pathways over 16 weeks. Titration to maximal tolerated dose of initial therapy (amitriptyline, duloxetine, or pregabalin) occurred during the first six weeks with subsequent supplementation (pregabalin in the first two groups, amitriptyline in the final group) over the following ten weeks if symptoms were inadequately controlled. Mean pain intensity decreased from 6.6 (on a 10-point scale) to 3.3 during the final week of each pathway, with no significant differences between pathways at any point. While about 35% achieved adequate pain relief with monotherapy, an additional 15% achieved this threshold with the supplemental second agent. While this study has the potential to change practice, it is worth noting that the known side effects of these drug classes were seen frequently during the study. Additionally, the lack of both a placebo control and investigation of sequential monotherapy (switching from one class of medication to another prior to combination therapy) may limit the study’s impact.

References: Diabetic Neuropathy Treatment

Drug-resistant tuberculosis is a driving factor behind the continued worldwide tuberculosis epidemic. In addition, tuberculosis treatment regimens are often lengthy and burdensome for patients, lasting between 9 and 24 months and involving multiple drugs with serious adverse cardiac, hepatic, and neurologic effects. A study in 2020 showed that the combination of bedaquiline (a diarylquinoline medication that targets the ATP synthase enzyme of TB mycobacteria), pretomanid (a nitroimidazole, a novel class of anti-bacterial agents developed by the TB Alliance), and linezolid 1200mg for 26 weeks resulted in a microbiologic cure of > 90%, but with significant rates of linezolid toxicity. In a follow up study, investigators examined rates of cure if the linezolid dosing were 1200mg for 9 or 26 weeks or 600mg for 9 or 26 weeks. Rates of clinical cure were 93% for the 1200mg-26 weeks cohort, 89% for the 1200mg-9 weeks cohort, 91% for the 600mg-26 weeks cohort, and 84% for the 600mg-9 weeks cohort. While adverse effects were still a significant concern in the study, the authors and editorialists – and subsequently the WHO in May 2022 – endorsed the combination of bedaquiline, pretomanid, and linezolid 600mg for 26 weeks (BPL 600-26, for short) as an appropriate alternative to lengthier treatment regimens for multi-drug resistant tuberculosis.

References: Drug-Resistant Tuberculosis