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- Norberg, Helena, 1984-
(författare)
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Bridging the gap between clinical trials and clinical practice : sacubitril-valsartan in heart failure as a model
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When novel treatments prove more effective than standard therapies, a swift and effective implementation is needed to reach cost-effectiveness and to benefit eligible patients. Meanwhile, women and elderly are often under-represented in clinical trials, which creates a knowledge gap on how to optimize treatment in clinical practice. The arrival of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan to patients with chronic heart failure and reduced ejection fraction (HFrEF) offered an opportunity to develop and test a new systematic introduction approach, as well as to investigate eligibility and management of sacubitril-valsartan in clinical practice. The aims of this thesis were to investigate obstacles to implement sacubitril-valsartan in a real-world heart failure population, as well as to develop a systematic and effective method to implement novel treatments in patients with chronic disease.With an observational cross-sectional study design, patients were retrospectively included if they had a heart failure diagnosis, living within the Umeå University Hospital catchment area, and had at least one visit at the Heart Centre or Department of internal medicine between January 2010 and March 2016. Eligibility to sacubitril-valsartan was based on the enrollment criteria applied in the landmark trial, PARADIGM-HF. We showed that the primary obstacle to implement sacubitril-valsartan was that only a quarter of the real-world HFrEF population was eligible. The most prominent difference was that real-world patients were significantly older compared with the PARADIGM-HF population. Disproportionally many patients, especially women, were ineligible for sacubitril-valsartan due to intolerance of renin-angiotensin system inhibitors in target doses. With multivariable linear regression analyses, we showed that the lower target doses in women were explained by biological sex differences.Management of heart failure treatment involve many titration steps that risk stressing the resources of both healthcare and patients. We prospectively investigated a direct switch to maximum dose sacubitril-valsartan in patients who tolerated target dose renin-angiotensin system inhibitors (equivalent to enalapril 10 mg twice daily). We showed that the simplified introduction was safe and generally well tolerated during the first year.The systematic introduction approach is a seven-step procedure:1) define a few main criteria2) primary scan patients with the one or two main criteria using computerized medical records/databases/clinical registries3) identify patients applying the other predefined criteria4) evaluate if any examinations/laboratory test updates are required5) summon identified patients with an information letter6) discuss treatment with the patient and prescribe if appropriate7) follow-up on initiated therapy and evaluate the process.We evaluated the approach with a mixed method, including both a case study of the sacubitril-valsartan implementation and an interview study with qualitative content analysis. The new systematic introduction approach effectively implemented sacubitril-valsartan in clinical practice, by identifying eligible patients with limited resources and time. The patients were overall satisfied with the new approach and their confidence in healthcare was maintained.In conclusion, we found that the strict inclusion criteria in the PARADIGM-HF trial would exclude a majority of patients with heart failure if they are implemented and that these criteria have an inherent bias versus the old and the frail, which in turn disproportionately affects women. We further found that patients who are on maximum recommended dose of renin-angiotensin system inhibitors can be safely switched to maximum dose sacubitril-valsartan and that our method of systematic introduction was effective in implementing sacubitril-valsartan to a heart failure population.The approach is a promising example of how to reduce the gap between clinical trials and clinical practice in patients with chronic disease.
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| 2. |
- Darehed, David, 1986-
(författare)
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The impact of organizational and temporal factors on acute stroke care in Sweden
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Acute stroke carries a high risk of morbidity and death, but early treatment can improve outcomes. Intravenous stroke thrombolysis (IVT) is one such treatment, it is however time-sensitive and show better outcomes the sooner it is given. Most studies on time to IVT so far have looked at fixed time-intervals, and studies of short delays in clinical practice are relatively scarce. Another well-established treatment is managing acute stroke patients in stroke units (SU). Admission rates to a SU as first destination of hospital care have improved over time in Sweden. In the past decade however, the rates have leveled out at around 75-80% without further improvement. A hypothesis is that in-hospital overcrowding contributes. Previous studies have shown that outcomes after stroke differ between hospital types, and also vary depending on time of admission, with higher mortality seen for off-hours, weekend and winter admissions. The reasons behind temporal variations are not fully understood, but it has been proposed that environmental, patient-related and organizational factors contribute. The overall aim of this thesis was to study the effect of organizational factors on quality of care and outcomes after stroke, primarily focusing on the role of in-hospital overcrowding, in-hospital time to IVT and time of admission, while also studying differences between hospitals.Methods: All papers in this thesis were based on data from the Swedish stroke register (Riksstroke), a national quality register that holds data on patient related factors, acute care and outcomes. Paper I included 13,955 patient admissions from 14 hospitals in Region Norrbotten and Region Skåne from 2011-2014, enriched with data on in-hospital bed occupancy. Papers II-IV included all 72 Swedish hospitals caring for patients with acute stroke. Paper II included data from 2011-2015 (N=113,862), paper III from 2011-2016 (N=132,744) and paper IV from 2010-2017 (N=14,132). Analyses included descriptive statistics, unadjusted analyses and multivariable adjusted analyses.Results: We found that each percent increase in in-hospital bed occupancy above 85% decreased admission rates to a SU as first destination of hospital care by 1.5% (odds ratio (OR) 0.985, 95% confidence interval (CI) 0.978-0.992), with significant differences between hospitals. Admission rates were also lower off-hours, compared to on-hours (OR 0.73, 95% CI 0.70-0.75). Over time, admission rates to a SU as first destination of hospital care decreased in university hospitals, while they increased in specialized non-university hospitals and community hospitals. Each minute delay in door-to-needle time (DNT) decreased the odds of 90-day survival by 0.6% (OR 0.994, 95% CI 0.992-0.996), increased the odds of ICH within 36 hours by 0.3% (OR 1.003, 95% CI 1.000-1.006), and led to significantly higher odds of a worsening in functional outcomes at 3 months by 0.3-0.4%. DNT within 30 minutes was most likely daytime, and varied between hospital types. 90-day survival was lowest for patients admitted in January (81.5%), and highest for those admitted in May (84.1%) (OR 1.28, 95% CI 1.17-1.40).Conclusion: We found that in-hospital overcrowding decrease admission rates to a SU as first destination of hospital care, and that even short delays in DNT decreases survival, increases ICH complications and leads to a worsening in functional outcomes in routine clinical practice. We also found that quality of care varied depending on time of admission and between hospitals, indicating unequal care. Organizational differences should be accessible through quality improvement efforts aiming to implement robust local guidelines for in-hospital stroke treatment.
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