Research Spotlight

Moore, A. Y., J. E. M. Charles and S. Moore (2019). “Sarecycline: a narrow spectrum tetracycline for the treatment of moderate-to-severe acne vulgaris.” Future Microbiol Sep 2. [Epub ahead of print].

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Sarecycline is a novel, narrow-spectrum, once-daily tetracycline-derived oral antibiotic that is FDA-approved in the US to be taken with or without food for moderate-to-severe acne vulgaris for ages 9 years of age and older. Sarecycline possesses anti-inflammatory properties and potent activity against Gram-positive bacteria, including activity against multiple strains of Cutibacterium acnes, while exhibiting minimal activity against enteric aerobic Gram-negative bacteria. Unlike many acne studies, sarecycline was investigated for chest and back acne. Significant reduction in inflammatory lesions was seen at week 12 at 1.5 mg/kg/day of sarecycline, with statistically significant improvement seen as early as week 3. No reports of phototoxicity, dizziness, pseudotumor cerebri or lupus but 1.2% nausea and 1.2% vaginal candidiasis was reported in the pivotal Phase III studies.

Malik, A., R. Masson, S. Singh, W. C. Wu, M. Packer, B. Pitt, F. Waagstein, C. J. Morgan, R. M. Allman, G. C. Fonarow and A. Ahmed (2019). “Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.” J Am Coll Cardiol 74(5): 617-627.

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BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF less-than-or-equal-to 45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

Malec, J. F., J. M. Ketchum, F. M. Hammond, J. D. Corrigan, K. Dams-O’Connor, T. Hart, T. Novack, M. Dahdah, G. G. Whiteneck and J. Bogner (2019). “Longitudinal Effects of Medical Comorbidities on Functional Outcome and Life Satisfaction After Traumatic Brain Injury: An Individual Growth Curve Analysis of NIDILRR Traumatic Brain Injury Model System Data.” J Head Trauma Rehabil 34(5): E24-e35.

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OBJECTIVE: To explore associations of specific physical and neuropsychiatric medical conditions to motor and cognitive functioning and life satisfaction over the first 10 years following traumatic brain injury (TBI). SETTING: Telephone follow-up through 6 TBI Model System centers. PARTICIPANTS: In total, 404 individuals or proxies with TBI enrolled in the TBI Model System longitudinal study participating in 10-year follow-up. DESIGN: Individual growth curve analysis. MAIN MEASURES: FIM Motor and Cognitive subscales, Satisfaction With Life Scales, and Medical and Mental Health Comorbidities Interview. RESULTS: Hypertension, diabetes, cancers, rheumatoid arthritis, and anxiety negatively affected the trajectory of motor functioning over time. Diabetes, cancers, chronic bronchitis, anxiety, and depression negatively impacted cognitive functioning. Numerous neuropsychiatric conditions (sleep disorder, alcoholism, drug addiction, anxiety, panic attacks, posttraumatic stress disorder, depression, and bipolar disorder), as well as hypertension, liver disease, and cancers, diminished life satisfaction. Other medical conditions had a negative effect on functioning and satisfaction at specific follow-up periods. CONCLUSION: Natural recovery after TBI may include delayed onset of functional decline or early recovery, followed by progressive deterioration, and is negatively affected by medical comorbidities. Results contribute to the growing evidence that TBI is most appropriately treated as a chronic medical condition complicated by a variety of comorbid conditions.

Lam, P. H., M. Packer, G. C. Fonarow, C. Faselis, R. M. Allman, C. J. Morgan, S. Singh, B. Pitt and A. Ahmed (2019). “Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.” Am J Med Aug 8. [Epub ahead of print].

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BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by post-randomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (HFrEF; ejection fraction less-than-or-equal-to 35%) were randomized to receive starting doses (5-10mg/day) of placebo (n=1284) or enalapril (n=1285). At day 14, both study drugs were blindly up-titrated to the target dose (20mg/day). Overall, 89% (2284/2569) of the patients returned for dose up-titration, which was achieved in 56% (1444/2248), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06) 0.82, respectively. Corresponding HRs (95% CIs) at 30days were (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68). The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.

Ko, J. M., K. S. White, A. H. Kovacs, K. M. Tecson, S. Apers, K. Luyckx, C. Thomet, W. Budts, J. Enomoto, M. A. Sluman, J. K. Wang, J. L. Jackson, P. Khairy, S. C. Cook, S. Chidambarathanu, L. Alday, K. Eriksen, M. Dellborg, M. Berghammer, B. Johansson, A. S. Mackie, S. Menahem, M. Caruana, G. Veldtman, A. Soufi, S. M. Fernandes, E. Callus, S. Kutty, P. Moons and A. M. Cedars (2019). “Differential impact of physical activity type on depression in adults with congenital heart disease: A multi-center international study.” J Psychosom Res 124: 109762.

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OBJECTIVE: This study aimed to examine the association between physical activity (PA) and depression in a large international cohort of adults with congenital heart disease (ACHD) as data about the differential impact of PA type on depression in this population are lacking. METHODS: In 2018, we conducted a cross-sectional assessment of 3908 ACHD recruited from 24 ACHD-specialized centers in 15 countries between April 2013 to March 2015. The Hospital Anxiety and Depression Scale was used to assess self-reported depressive symptoms and the Health-Behavior Scale-Congenital Heart Disease was used to collect PA information. Cochran-Armitage tests were performed to assess trends between depressive symptom levels and PA participation. Chi-Square and Wilcoxon Rank Sum tests were utilized to examine relations between depressive symptom levels and patient characteristics. Stepwise multivariable models were then constructed to understand the independent impact of PA on depressive symptoms. RESULTS: The overall prevalence of elevated depressive symptoms in this sample was 12% with significant differences in rates between countries (p<.001). Physically active individuals were less likely to be depressed than those who were sedentary. Of the 2 PA domains examined, sport participation rather than active commute was significantly associated with reduced symptoms of depression. After adjustment in multivariable analysis, sport participation was still significantly associated with 38% decreased probability of depressive symptoms (p<.001). CONCLUSIONS: Sport participation is independently associated with reduced depressive symptoms. The development and promotion of sport-related exercise prescriptions uniquely designed for ACHD may improve depression status in this unique population.