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Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass.
We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass.
We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety.
In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.
During the Randomized Assessment of Rapid Endovascular Treatment (EVT) of Ischemic Stroke (ESCAPE) trial, patient-level micro-costing data were collected. We report a cost-effectiveness analysis of EVT, using ESCAPE trial data and Markov simulation, from a universal, single-payer system using a societal perspective over a patient’s lifetime.
Primary data collection alongside the ESCAPE trial provided a 3-month trial-specific, non-model, based cost per quality-adjusted life year (QALY). A Markov model utilizing ongoing lifetime costs and life expectancy from the literature was built to simulate the cost per QALY adopting a lifetime horizon. Health states were defined using the modified Rankin Scale (mRS) scores. Uncertainty was explored using scenario analysis and probabilistic sensitivity analysis.
The 3-month trial-based analysis resulted in a cost per QALY of $201,243 of EVT compared to the best standard of care. In the model-based analysis, using a societal perspective and a lifetime horizon, EVT dominated the standard of care; EVT was both more effective and less costly than the standard of care (−$91). When the time horizon was shortened to 1 year, EVT remains cost savings compared to standard of care (∼$15,376 per QALY gained with EVT). However, if the estimate of clinical effectiveness is 4% less than that demonstrated in ESCAPE, EVT is no longer cost savings compared to standard of care.
Results support the adoption of EVT as a treatment option for acute ischemic stroke, as the increase in costs associated with caring for EVT patients was recouped within the first year of stroke, and continued to provide cost savings over a patient’s lifetime.
Acute ischemic stroke may affect women and men differently. We aimed to evaluate sex differences in outcomes of endovascular treatment (EVT) for ischemic stroke due to large vessel occlusion in a population-based study in Alberta, Canada.
Methods and Results:
Over a 3-year period (April 2015–March 2018), 576 patients fit the inclusion criteria of our study and constituted the EVT group of our analysis. The medical treatment group of the ESCAPE trial had 150 patients. Thus, our total sample size was 726. We captured outcomes in clinical routine using administrative data and a linked database methodology. The primary outcome of our study was home-time. Home-time refers to the number of days that the patient was back at their premorbid living situation without an increase in the level of care within 90 days of the index stroke event. In adjusted analysis, EVT was associated with an increase of 90-day home-time by an average of 6.08 (95% CI −2.74–14.89, p-value 0.177) days in women compared to an average of 11.20 (95% CI 1.94–20.46, p-value 0.018) days in men. Further analysis revealed that the association between EVT and 90-day home-time in women was confounded by age and onset-to-treatment time.
We found a nonsignificant nominal reduction of 90-day home-time gain for women compared to men in this province-wide population-based study of EVT for large vessel occlusion, which was only partially explained by confounding.
Decisions to treat large-vessel occlusion with endovascular therapy (EVT) or intravenous alteplase depend on how physicians weigh benefits against risks when considering patients’ comorbidities. We explored EVT/alteplase decision-making by stroke experts in the setting of comorbidity/disability.
In an international multi-disciplinary survey, experts chose treatment approaches under current resources and under assumed ideal conditions for 10 of 22 randomly assigned case scenarios. Five included comorbidities (cancer, cardiac/respiratory/renal disease, mild cognitive impairment [MCI], physical dependence). We examined scenario/respondent characteristics associated with EVT/alteplase decisions using multivariable logistic regressions.
Among 607 physicians (38 countries), EVT was chosen less often in comorbidity-related scenarios (79.6% under current resources, 82.7% assuming ideal conditions) versus six “level-1A” scenarios for which EVT/alteplase was clearly indicated by current guidelines (91.1% and 95.1%, respectively, odds ratio [OR] [current resources]: 0.38, 95% confidence interval 0.31–0.47). However, EVT was chosen more often in comorbidity-related scenarios compared to all other 17 scenarios (79.6% versus 74.4% under current resources, OR: 1.34, 1.17–1.54). Responses favoring alteplase for comorbidity-related scenarios (e.g. 75.0% under current resources) were comparable to level-1A scenarios (72.2%) and higher than all others (60.4%). No comorbidity independently diminished EVT odds when considering all scenarios. MCI and dependence carried higher alteplase odds; cancer and cardiac/respiratory/renal disease had lower odds. Being older/female carried lower EVT odds. Relevant respondent characteristics included performing more EVT cases/year (higher EVT-, lower alteplase odds), practicing in East Asia (higher EVT odds), and in interventional neuroradiology (lower alteplase odds vs neurology).
Moderate-to-severe comorbidities did not consistently deter experts from EVT, suggesting equipoise about withholding EVT based on comorbidities. However, alteplase was often foregone when respondents chose EVT. Differences in decision-making by patient age/sex merit further study.
Emergency Medical Services (EMS) systems have developed protocols for prehospital activation of the cardiac catheterization laboratory for patients with suspected ST-elevation myocardial infarction (STEMI) to decrease first-medical-contact-to-balloon time (FMC2B). The rate of “false positive” prehospital activations is high. In order to decrease this rate and expedite care for patients with true STEMI, the American Heart Association (AHA; Dallas, Texas USA) developed the Mission Lifeline PreAct STEMI algorithm, which was implemented in Los Angeles County (LAC; California USA) in 2015. The hypothesis of this study was that implementation of the PreAct algorithm would increase the positive predictive value (PPV) of prehospital activation.
This is an observational pre-/post-study of the effect of the implementation of the PreAct algorithm for patients with suspected STEMI transported to one of five STEMI Receiving Centers (SRCs) within the LAC Regional System. The primary outcome was the PPV of cardiac catheterization laboratory activation for percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The secondary outcome was FMC2B.
A total of 1,877 patients were analyzed for the primary outcome in the pre-intervention period and 405 patients in the post-intervention period. There was an overall decrease in cardiac catheterization laboratory activations, from 67% in the pre-intervention period to 49% in the post-intervention period (95% CI for the difference, -14% to -22%). The overall rate of cardiac catheterization declined in post-intervention period as compared the pre-intervention period, from 34% to 30% (95% CI, for the difference -7.6% to 0.4%), but actually increased for subjects who had activation (48% versus 58%; 95% CI, 4.6%-15.0%). Implementation of the PreAct algorithm was associated with an increase in the PPV of activation for PCI or CABG from 37.9% to 48.6%. The overall odds ratio (OR) associated with the intervention was 1.4 (95% CI, 1.1-1.8). The effect of the intervention was to decrease variability between medical centers. There was no associated change in average FMC2B.
The implementation of the PreAct algorithm in the LAC EMS system was associated with an overall increase in the PPV of cardiac catheterization laboratory activation.
Covert brain infarcts (CBIs) are five times more prevalent than symptomatic brain infarcts. CBIs are associated with cognitive impairment and therefore may be a target for preventing cognitive decline and dementia. This review focuses on strategies for preventing CBI-related cognitive impairment, either by preventing incident or recurrent CBI or by enhancing cognitive reserve. CBIs begin to become prevalent during midlife and are highly prevalent in later life. The distribution of vascular pathologies of CBI differs from those that cause symptomatic stroke; therefore, preventive treatments may need to differ as well. Only a few randomized clinical trials have provided data on CBI prevention, without conclusive results. Limited data suggest that higher early-life education, hypothesized to enhance cognitive reserve, can protect the brain from effects of CBI.
The Single Ventricle Reconstruction Trial randomised neonates with hypoplastic left heart syndrome to a shunt strategy but otherwise retained standard of care. We aimed to describe centre-level practice variation at Fontan completion.
Centre-level data are reported as median or median frequency across all centres and range of medians or frequencies across centres. Classification and regression tree analysis assessed the association of centre-level factors with length of stay and percentage of patients with prolonged pleural effusion (>7 days).
The median Fontan age (14 centres, 320 patients) was 3.1 years (range from 1.7 to 3.9), and the weight-for-age z-score was −0.56 (−1.35 + 0.44). Extra-cardiac Fontans were performed in 79% (4–100%) of patients at the 13 centres performing this procedure; lateral tunnels were performed in 32% (3–100%) at the 11 centres performing it. Deep hypothermic circulatory arrest (nine centres) ranged from 6 to 100%. Major complications occurred in 17% (7–33%). The length of stay was 9.5 days (9–12); 15% (6–33%) had prolonged pleural effusion. Centres with fewer patients (<6%) with prolonged pleural effusion and fewer (<41%) complications had a shorter length of stay (<10 days; sensitivity 1.0; specificity 0.71; area under the curve 0.96). Avoiding deep hypothermic circulatory arrest and higher weight-for-age z-score were associated with a lower percentage of patients with prolonged effusions (<9.5%; sensitivity 1.0; specificity = 0.86; area under the curve 0.98).
Fontan perioperative practices varied widely among study centres. Strategies to decrease the duration of pleural effusion and minimise complications may decrease the length of stay. Further research regarding deep hypothermic circulatory arrest is needed to understand its association with prolonged pleural effusion.
Alteplase is an effective treatment for ischaemic stroke patients, and it is widely available at all primary stroke centres. The effectiveness of alteplase is highly time-dependent. Large tertiary centres have reported significant improvements in their door-to-needle (DTN) times. However, these same improvements have not been reported at community hospitals.
Red Deer Regional Hospital Centre (RDRHC) is a community hospital of 370 beds that serves approximately 150,000 people in their acute stroke catchment area. The RDRHC participated in a provincial DTN improvement initiative, and implemented a streamlined algorithm for the treatment of stroke patients. During this intervention period, they implemented the following changes: early alert of an incoming acute stroke patient to the neurologist and care team, meeting the patient immediately upon arrival, parallel work processes, keeping the patient on the Emergency Medical Service stretcher to the CT scanner, and administering alteplase in the imaging area. Door-to-needle data were collected from July 2007 to December 2017.
A total of 289 patients were treated from July 2007 to December 2017. In the pre-intervention period, 165 patients received alteplase and the median DTN time was 77 minutes [interquartile range (IQR): 60–103 minutes]; in the post-intervention period, 104 patients received alteplase and the median DTN time was 30 minutes (IQR: 22–42 minutes) (p < 0.001). The annual number of patients that received alteplase increased from 9 to 29 in the pre-intervention period to annual numbers of 41 to 63 patients in the post-intervention period.
Community hospitals staffed with community neurologists can achieve median DTN times of 30 minutes or less.
The impact of losing a limb in military service extends well beyond initial recovery and rehabilitation, with long-term consequences and challenges requiring health-care commitments across the lifecourse. This paper presents a systematic review of the current state of knowledge regarding the long-term impact of ageing and limb-loss in military veterans. Key databases were systematically searched including: ASSIA, CINAHL, Cochrane Library, Medline, Web of Science, PsycArticles/PsychInfo, ProQuest Psychology and ProQuest Sociology Journals, and SPORTSDiscus. Empirical studies which focused on the long-term impact of limb-loss and/or health-care requirements in veterans were included. The search process revealed 30 papers relevant for inclusion. These papers focused broadly on four themes: (a) long-term health outcomes, prosthetics use and quality of life; (b) long-term psycho-social adaptation and coping with limb-loss; (c) disability and identity; and (d) estimating the long-term costs of care and prosthetic provision. Findings present a compelling case for ensuring the long-term care needs and costs of rehabilitation for older limbless veterans are met. A dearth of information on the lived experience of limb-loss and the needs of veterans’ families calls for further research to address these important issues.
In this brief report, computed tomography perfusion (CTP) thresholds predicting follow-up infarction in patients presenting <3 hours from stroke onset and achieving ultra-early reperfusion (<45 minutes from CTP) are reported. CTP thresholds that predict follow-up infarction vary based on time to reperfusion: Tmax >20 to 23 seconds and cerebral blood flow <5 to 7 ml/min−1/(100 g)−1 or relative cerebral blood flow <0.14 to 0.20 optimally predicted the final infarct. These thresholds are stricter than published thresholds.
Silent pulmonary embolism (PE) may be associated with acute ischemic stroke (AIS). We identified 10 patients from 3,132 unique patients (3,431 CT scans). We retrospectively examined CT angiogram of patients with AIS to determine the frequency of concurrent PE in AIS. The period prevalence of PE was 0.32. Seven patients had concurrent PE, whereas three had PE diagnosed 2 days after their AIS presentation. We suspected paradoxical embolism via patent foramen ovale as the cause of stroke in three patients and thrombophilia in four patients. Seven patients had poor outcome including four deaths. CT angiogram stroke protocol images from aortic arch to vertex allows visualization of upper pulmonary arteries and PE detection in AIS.
Background: Stroke patients of lower socioeconomic status have worse outcomes. It remains poorly understood whether this is due to illness severity or personal or health system barriers. We explored the experiences of stroke patients with financial barriers in a qualitative descriptive pilot study, seeking to capture perceived challenges that interfere with their poststroke health and recovery. Methods: We interviewed six adults with a history of stroke and financial barriers in Alberta, Canada, inquiring about their: (1) experiences after stroke; (2) experience of financial barriers; (3) perceived reasons for financial barriers; (4) health consequences of financial barriers; and (5) mechanisms for coping with financial barriers. Two reviewers analyzed data using inductive thematic analysis. Results: The participants developed new or worsened financial circumstances as a consequence of stroke-related disability. Poststroke impairments and financial barriers took a toll on their mental health. They struggled to access several aspects of long-term poststroke care, including allied health professional services, medications, and proper nutrition. They described opportunity costs and tradeoffs when accessing health services. In several cases, they were unaware of health resources available to them and were hesitant to disclose their struggles to their physicians and even their families. Conclusion: Some patients with financial barriers perceive challenges to accessing various aspects of poststroke care. They may have inadequate knowledge of resources available to them and may not disclose their concerns to their health care team. This suggests that providers themselves might consider asking stroke patients about financial barriers to optimize their long-term poststroke care.
The aim of this study was to describe previously unrecognised or under-recognised adverse events associated with Melody® valve implantation.
In rare diseases and conditions, it is typically not feasible to conduct large-scale safety trials before drug or device approval. Therefore, post-market surveillance mechanisms are necessary to detect rare but potentially serious adverse events.
We reviewed the United States Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database and conducted a structured literature review to evaluate adverse events associated with on- and off-label Melody® valve implantation. Adverse events were compared with those described in the prospective Investigational Device Exemption and Post-Market Approval Melody® transcatheter pulmonary valve trials.
We identified 631 adverse events associated with “on-label” Melody® valve implants and 84 adverse events associated with “off-label” implants. The most frequent “on-label” adverse events were similar to those described in the prospective trials including stent fracture (n=210) and endocarditis (n=104). Previously unrecognised or under-recognised adverse events included stent fragment embolisation (n=5), device erosion (n=4), immediate post-implant severe valvar insufficiency (n=2), and late coronary compression (n=2 cases at 5 days and 3 months after implantation). Under-recognised adverse events associated with off-label implantation included early valve failure due to insufficiency when implanted in the tricuspid position (n=7) and embolisation with percutaneous implantation in the mitral position (n=5).
Post-market passive surveillance does not demonstrate a high frequency of previously unrecognised serious adverse events with “on-label” Melody® valve implantation. Further study is needed to evaluate safety of “off-label” uses.
Background: Stroke is often preceded by transient symptoms. Although global stroke rates have been shown to be declining, previous studies have reported inconsistent temporal trends of transient ischemic attacks (TIA). The objective of the current study is to report the temporal trends of TIA admissions and outcomes in Canada over the last 11 years. Methods: We conducted a complete population cohort study using a national administrative database to study the temporal trend of age- and sex-adjusted TIA admission rates in Canada from 2003 to 2013. We also determined the rates of TIA and stroke diagnoses in the emergency department in the province of Ontario during the same period. We used multivariable analyses to study discharge location after acute hospitalization as well as 90-day stroke and/or TIA readmission rates. Results: Of 425,799 admissions to an acute care hospital for all stroke and TIA, 71,443 (16.8%) were TIA. The age- and sex-standardized rates of TIA admission decreased significantly during the study period from 30.0 to 20.6 per 100,000 (p<0.0001). In Ontario, decreasing TIA admissions is mirrored by decreasing rates of TIA directly discharged from the emergency department (55.1 to 46.8 per 100,000, p = 0.002). The odds of 90-day readmission rates for stroke or TIA are also decreasing (adjusted odds ratio, 0.97; 95% confidence interval, 0.96-0.99). Conclusions: We show that TIA admission rates have declined in the past 11 years in Canada, reflecting improved vascular risk reduction and stroke care. Future studies to confirm our findings on improved stroke or TIA recurrence rates are necessary.
Background: Interhospital transfer is an important but resource-intensive pattern of care. The use for stroke patients is highly dependent upon health system structure. We examined the impact of hospital transfers for stroke care in Canada. Methods: We analyzed hospital administrative data within the Canadian Institute for Health Information (CIHI) Database for the 3 fiscal years 2011/12, 2012/13 and 2013/14. Patients with clinical stroke syndrome (ischemic or hemorrhagic) were identified using International Classification of Diseases. Stroke centers were defined by Heart & Stroke Foundation of Canada stroke report. Results: During the 3-year period,397 patients in Canada (excluding Quebec) were admitted to hospital for clinical stroke syndrome. Median age was 75 (interquartile range [IQR] 64–84) years; 50.6 % were male. Less than 5% (n=4030) of patients were transferred. Patients transferred to stroke centers were younger (p<0.001) and had shorter median length of stay (p<0.001). The highest probability of discharge home was associated with sole care at stroke center (43.8%). Transfer to stroke center from community hospital had the highest probability for discharge to rehabilitation facility (25%) and lowest to either long-term (2.1%) or complex community care (2.0%). Transferred patients had lower mortality at discharge. Conclusion: Younger patients were transferred more frequently to stroke centers; older patients were more likely treated in community hospitals. Sole stroke center care was associated with high discharge rate to home; transfer to a stroke center was associated with high discharge rate to rehabilitation and lower mortality rates.
The aim of the study was to evaluate the trends in respiratory syncytial virus-related hospitalisations and associated outcomes in children with haemodynamically significant heart disease in the United States of America.
The Kids’ Inpatient Databases (1997–2012) were used to estimate the incidence of respiratory syncytial virus hospitalisation among children ⩽24 months with or without haemodynamically significant heart disease. Weighted multivariable logistic regression and chi-square tests were used to evaluate the trends over time and factors associated with hospitalisation, comparing eras before and after publication of the 2003 American Academy of Pediatrics palivizumab immunoprophylaxis guidelines. Secondary outcomes included in-hospital mortality, morbidity, length of stay, and cost.
Overall, 549,265 respiratory syncytial virus-related hospitalisations were evaluated, including 2518 (0.5%) in children with haemodynamically significant heart disease. The incidence of respiratory syncytial virus hospitalisation in children with haemodynamically significant heart disease decreased by 36% when comparing pre- and post-palivizumab guideline eras versus an 8% decline in children without haemodynamically significant heart disease (p<0.001). Children with haemodynamically significant heart disease had higher rates of respiratory syncytial virus-associated mortality (4.9 versus 0.1%, p<0.001) and morbidity (31.5 versus 3.5%, p<0.001) and longer hospital length of stay (17.9 versus 3.9 days, p<0.001) compared with children without haemodynamically significant heart disease. The mean cost of respiratory syncytial virus hospitalisation in 2009 was $58,166 (95% CI:$46,017, $70,315).
These data provide stakeholders with a means to evaluate the cost–utility of various immunoprophylaxis strategies.
Although intravenous thrombolysis increases the probability of a good
functional outcome in carefully selected patients with acute ischemic
stroke, a substantial proportion of patients who receive thrombolysis do not
have a good outcome. Several recent trials of mechanical thrombectomy appear
to indicate that this treatment may be superior to thrombolysis. We
therefore conducted a systematic review and meta-analysis to evaluate the
clinical effectiveness and safety of new-generation mechanical thrombectomy
devices with intravenous thrombolysis (if eligible) compared with
intravenous thrombolysis (if eligible) in patients with acute ischemic
stroke caused by a proximal intracranial occlusion. We systematically
searched seven databases for randomized controlled trials published between
January 2005 and March 2015 comparing stent retrievers or thromboaspiration
devices with best medical therapy (with or without intravenous thrombolysis)
in adults with acute ischemic stroke. We assessed risk of bias and overall
quality of the included trials. We combined the data using a fixed or random
effects meta-analysis, where appropriate. We identified 1579 studies; of
these, we evaluated 122 full-text papers and included five randomized
control trials (n=1287). Compared with patients treated medically, patients
who received mechanical thrombectomy were more likely to be functionally
independent as measured by a modified Rankin score of 0-2 (odds ratio, 2.39;
95% confidence interval, 1.88-3.04; I2=0%). This finding was
robust to subgroup analysis. Mortality and symptomatic intracerebral
hemorrhage were not significantly different between the two groups.
Mechanical thrombectomy significantly improves functional independence in
appropriately selected patients with acute ischemic stroke.