Research Spotlight

Vaduganathan, M., B. L. Claggett, A. S. Desai, S. D. Anker, S. V. Perrone, S. Janssens, D. Milicic, J. L. Arango, M. Packer, V. C. Shi, M. P. Lefkowitz, J. J. V. McMurray and S. D. Solomon (2019). “Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared with Valsartan in HFpEF.” J Am Coll Cardiol Nov 6. [Epub ahead of print].

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BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: To determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to HF hospitalization among patients with HF and preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF, we assessed risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (>/=45%). Primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2,490 (52%) were never previously hospitalized. Over median 35 months follow-up, risk of total HF hospitalizations and cardiovascular death was inversely and non-linearly associated with timing from prior HF hospitalization (P<0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio 0.73; 95% confidence interval 0.53-0.99) to patients never hospitalized (rate ratio 1.00; 95% confidence interval 0.80-1.24); trend in relative risk reduction Pinteraction=0.15. With valsartan alone, rate of total primary events was 26.7 (180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (180 days or who were never hospitalized; trend in absolute risk reduction Pinteraction=0.050. CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high-risk for near-term clinical progression. In the PARAGON-HF trial, relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrants prospective validation.

Tatachar, A., L. C. Cole, H. L. Nguyen and K. Heinrich (2019). “Evaluation of pharmacy-based telephone interventions on medication pick-up rates: a retrospective, quality improvement study at charity outpatient clinics.” Int J Pharm Pract 27(6): 510-519.

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OBJECTIVES: To evaluate a live telephonic outreach intervention made by clinical pharmacists and clinical pharmacy technicians on medication pick-up rates. METHODS: A retrospective, quality improvement study conducted at six outpatient charity clinics in Dallas-Fort Worth area between 1 January 2017 and 31 July 2017. A live telephonic call was made by a pharmacy team member if the patient did not pick-up at least one prescription item. Patients may receive more than one call if they did not pick-up medication(s) more than once during the study period. A live telephonic call resulted in three categories: contacted, left a voice message and unable to contact. Medication pick-up rates were obtained from a pharmacy claims database. KEY FINDINGS: The study population included 1726 individual patients who failed to pick-up at least one medication from Baylor Scott & White Health pharmacy. A total of 2551 live telephonic calls were made for the study population. A total of 1175 live telephonic calls (46.1%, n = 2551) resulted in a patient picking up medication(s). Results from the generalized estimating equation logistic regression models showed that patients who received a voice message (OR: 1.37; 95% CI: 1.05 to 1.80; P < 0.021) or was contacted (OR: 1.99; 95% CI: 1.54 to 2.60; P < 0.001) were more likely to pick-up their medications as compared to the 'unable to contact' group. CONCLUSIONS: Telephonic interventions from the pharmacy team can serve as a successful means to increase medication pick-up rates among charity clinic patients.

Tapper, E. B. and R. S. Rahimi (2019). “Low-Value Levels: Ammonia Testing Does Not Improve the Outcomes of Overt Hepatic Encephalopathy.” Am J Gastroenterol Nov 8. [Epub ahead of print].

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Hepatic encephalopathy is a clinical diagnosis. However, many clinicians measure ammonia levels in hospitalized patients presenting with hepatic encephalopathy. In this editorial, we review the results of an important study by Haj and Rockey (see Haj M and Rockey DC. Ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis. Am J Gastroenterol [Epub ahead of print October 14, 2019.]). The authors examined the management decisions effected affected by and outcomes associated with (i) ordering an ammonia level and (ii) knowing the ammonia level. They find found that ammonia level determination did not impact affect clinical decision-making or patient outcomes. These persuasive data demonstrate the limited clinical utility of ammonia levels and highlight the need for testing stewardship to dissuade unnecessary use through educational efforts and decision supports.

Steward, A. M., E. Wiggs, T. Lindstrom, S. Ukwuani, E. Ryan, N. Tayebi, T. Roshan Lal, G. Lopez, R. Schiffmann and E. Sidransky (2019). “Variation in cognitive function over time in Gaucher disease type 3.” Neurology Nov 12. [Epub ahead of print].

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OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.

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 (2019). “Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.” J Antimicrob Chemother Nov 12. [Epub ahead of print].

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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.