Research Spotlight

Swank, C., M. Trammell, L. Callender, M. Bennett, K. Patterson, J. Gillespie, P. Kapoor and S. Driver (2020). “The impact of a patient-directed activity program on functional outcomes and activity participation after stroke during inpatient rehabilitation-a randomized controlled trial.” Clin Rehabil Jan 15. [Epub ahead of print].

Full text of this article.

OBJECTIVE: Individuals post stroke are inactive, even during rehabilitation, contributing to ongoing disability and risk of secondary health conditions. Our aims were to (1) conduct a randomized controlled trial to examine the efficacy of a “Patient-Directed Activity Program” on functional outcomes in people post stroke during inpatient rehabilitation and (2) examine differences three months post inpatient rehabilitation discharge. DESIGN: Randomized control trial. SETTING: Inpatient rehabilitation facility. SUBJECTS: Patients admitted to inpatient rehabilitation post stroke. INTERVENTIONS: Patient-Directed Activity Program (PDAP) or control (usual care only). Both groups underwent control (three hours of therapy/day), while PDAP participants were prescribed two additional 30-minute activity sessions/day. MAIN MEASURES: Outcomes (Stroke Rehabilitation Assessment of Movement Measure, Functional Independence Measure, balance, physical activity, Stroke Impact Scale) were collected at admission and discharge from inpatient rehabilitation and three-month follow-up. RESULTS: Seventy-three patients (PDAP (n = 37); control (n = 36)) were included in the primary analysis. Patients in PDAP completed a total of 23.1 +/- 16.5 sessions (10.7 +/- 8.5 upper extremity; 12.4 +/- 8.6 lower extremity) during inpatient rehabilitation. No differences were observed between groups at discharge in functional measures. PDAP completed significantly more steps/day (PDAP = 657.70 +/- 655.82, control = 396.17 +/- 419.65; P = 0.022). The Stroke Impact Scale showed significantly better memory and thinking (PDAP = 86.2 +/- 11.4, control = 80.8 +/- 16.7; P = 0.049), communication (PDAP = 93.6 +/- 8.3, control = 89.6 +/- 12.4; P = 0.042), mobility (PDAP = 62.2 +/- 22.5, control = 53.8 +/- 21.8; P = 0.038), and overall recovery from stroke (PDAP = 62.1 +/- 19.1, control = 52.2 +/- 18.7; P = 0.038) for PDAP compared to control. At three months post discharge, PDAP (n = 11) completed significantly greater physical activity (P = 0.014; 3586.5 +/- 3468.5 steps/day) compared to control (n = 10; 1760.9 +/- 2346.3 steps/day). CONCLUSION: Functional outcome improvement was comparable between groups; however, PDAP participants completed more steps and perceived greater recovery.

Srivastava, S., D. Deshpande, G. Magombedze, J. van Zyl, K. Cirrincione, K. Martin, P. Bendet, A. Berg, D. Hanna, K. Romero, D. Hermann and T. Gumbo (2020). “Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.” J Antimicrob Chemother 75(2): 392-399.

Full text of this article.

OBJECTIVES: Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3-4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB). METHODS: A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen. RESULTS: Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13-0.23) versus 0.15 (95% credible interval=0.08-0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13-0.18) versus 0.11 (95% credible interval=0.09-0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1-41.34) and 72.30% (95% credible interval=71.41-73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18-94.13) at 6 months for standard therapy. CONCLUSIONS: The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.

Solomon, S. D., M. Vaduganathan, L. C. B, M. Packer, M. Zile, K. Swedberg, J. Rouleau, A. P. M, A. Desai, H. L. L, L. Kober, I. Anand, N. Sweitzer, G. Linssen, B. Merkely, J. Luis Arango, D. Vinereanu, C. H. Chen, M. Senni, A. Sibulo, S. Boytsov, V. Shi, A. Rizkala, M. Lefkowitz and J. J. V. McMurray (2020). “Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.” Circulation 141(5): 352-361.

Full text of this article.

BACKGROUND: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. METHODS: We combined data from PARADIGM-HF (LVEF eligibility/=45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: 22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. RESULTS: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. CONCLUSIONS: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Simpson, J., P. S. Jhund, L. H. Lund, S. Padmanabhan, B. L. Claggett, L. Shen, M. C. Petrie, W. T. Abraham, A. S. Desai, K. Dickstein, L. Kober, M. Packer, J. L. Rouleau, G. Mueller-Velten, S. D. Solomon, K. Swedberg, M. R. Zile and J. J. V. McMurray (2020). “Prognostic Models Derived in PARADIGM-HF and Validated in ATMOSPHERE and the Swedish Heart Failure Registry to Predict Mortality and Morbidity in Chronic Heart Failure.” JAMA Cardiol Jan 29. [Epub ahead of print].

Full text of this article.

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8011), and 70.6% were New York Heart Association class II (n = 5919 of 8011). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, beta-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by chi2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual’s risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

Silfvast-Kaiser, A. and M. A. Menter (2020). “How can we manage the safety concerns associated with the increase in biologics for psoriasis?” Expert Opin Drug Saf Jan 31. [Epub ahead of print].

Full text of this article.

Psoriasis is a chronic, systemic, inflammatory disease affecting 2–3% of the worldwide population. It is associated with multiple comorbidities including cardiovascular disease, metabolic syndrome, diabetes, obesity, arthritis, and negative psychosocial issues. Often, the choice of appropriate biologic therapy is driven by an individual’s comorbidities and conditions. The spectrum of biologic therapies for the treatment of moderate-to-severe plaque psoriasis (MTSPP) has expanded significantly over the past decade, exhibiting increasing efficacy and safety. Currently, eleven biologics are available for the treatment of MTSPP. These include 4 tumor necrosis factor-alpha (TNF-α) inhibitors, a single molecule targeting IL-12/IL-23 combination, 3 IL-17 agents, and 3 IL-23 agents. Each novel therapy exhibits its own benefit/risk profile and generally, less adverse effects than those of the older systemic non-biologic agents. Data suggest that most patients are likely to maintain effective and safe long-term treatment on these medications. Despite this, both patients and providers have important safety concerns . . . The field of biologic therapy continues to expand as our understanding of psoriasis and its immunopathogenesis increases. We fully expect therapies to continue becoming increasingly effective and specific. As the specificity of biologic therapies develops, biologic medications will become increasingly safe with less potential for adverse effect. Novel biologic therapies already show considerable promise in the treatment of psoriasis with clearance in up to 90% of patients. With more long-term data and newer agents, we can potentially effect improvement on the multiple systemic co-morbidities associated with psoriasis as well. Biomarker research could help clinicians individualize their approach to treating psoriasis in the future, allowing for even more optimization of treatment, safety, and efficacy in each individual patient. As the biologic armamentarium expands, the expectation is rising for clinicians to better understand the safety and efficacy of these medications. The future of biologics for psoriasis continues to be extremely bright. (Excerpts from text, n.p.; no abstract available.)