Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Background: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. Methods: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). Findings: Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80). Interpretation: Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care. Funding: The National Health and Medical Research Council of Australia

A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly

Background: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. Methods: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. Results: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. Conclusion: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. Trial Registration: The Australian Clinical Trials Registry ACTRN12607000387426 © 2014 MacIntyre et al

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

The prototype of a frailty learning health system: The HARMONY Model

AbstractIntroductionRapid translation of research findings into clinical practice through innovation is critical to improve health systems and patient outcomes. Access to efficient systems of learning underpinned with real‐time data are the future of healthcare. This type of health system will decrease unwarranted clinical variation, accelerate rapid evidence translation, and improve overall healthcare quality.MethodsThis paper aims to describe The HARMONY model (acHieving dAta‐dRiven quality iMprovement to enhance frailty Outcomes using a learNing health sYstem), a new frailty learning health system model of implementation science and practice improvement. The HARMONY model provides a prototype for clinical quality registry infrastructure and partnership within health care.ResultsThe HARMONY model was applied to the Western Sydney Clinical Frailty Registry as the prototype exemplar. The model networks longitudinal frailty data into an accessible and useable format for learning. Creating local capability that networks current data infrastructures to translate and improve quality of care in real‐time.ConclusionThis prototype provides a model of registry data feedback and quality improvement processes in an inpatient aged care and rehabilitation hospital setting to help reduce clinical variation, enhance research translation capacity, and improve care quality.</jats:sec

Inclusion of People With Aphasia in Stroke Trials: A Systematic Search and Review.

BACKGROUND: Although people with aphasia (PwA) represent 30% of stroke survivors, they are frequently excluded from stroke research, or their inclusion is unclear. Such practice significantly limits the generalizability of stroke research, increases the need to duplicate research in aphasia-specific populations, and raises important ethical and human rights issues. OBJECTIVE: To detail the extent and nature of inclusion of PwA in contemporary stroke randomized controlled trials (RCTs). METHODS: We conducted a systematic search to identify completed stroke RCTs and RCT protocols published in 2019. Web of Science was searched using terms "stroke" and "randomized controlled trial". These articles were reviewed by extracting rates of PwA inclusion/exclusion, whether "aphasia" or related terms were referred to in the article or supplemental files, eligibility criteria, consent procedures, adaptations made to support the inclusion of PwA, and attrition rates of PwA. Data were summarized, and descriptive statistics applied when appropriate. RESULTS: 271 studies comprising 215 completed RCTs and 56 protocols were included. 36.2% of included studies referred to aphasia/dysphasia. Of completed RCTs, only 6.5% explicitly included PwA, 4.7% explicitly excluded PwA, and inclusion was unclear in the remaining 88.8%. Among RCT protocols, 28.6% of studies intended inclusion, 10.7% intended excluding PwA, and in 60.7%, inclusion was unclear. In 45.8% of included studies, sub-groups of PwA were excluded, either explicitly (ie, particular types/severities of aphasia, eg, global aphasia) or implicitly, by way of ambiguous eligibility criteria which could potentially relate to a sub-group of PwA. Little rationale for exclusion was provided. 71.2% of completed RCTs did not report any adaptations that could support the inclusion of PwA, and minimal information was provided about consent procedures. Where it could be determined, attrition of PwA averaged 10% (range 0%-20%). CONCLUSION: This paper details the extent of inclusion of PwA in stroke research and highlights opportunities for improvement

Smoking influences outcome in patients who had thrombolysed ischaemic stroke: The ENCHANTED study

Background and purpose As studies vary in defining the prognostic significance of smoking in acute ischaemic stroke (AIS), we aimed to determine the relation of smoking and key outcomes in patient participants who had thrombolysed AIS of the international quasi-factorial randomised Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods Post-hoc analyses of ENCHANTED, an international quasi-factorial randomised evaluation of intravenous alteplase-dose comparison and levels of blood pressure control in patients who had thrombolysed AIS. Multivariable logistic regression models with inverse probability of treatment weighting (IPTW) propensity scores were used to determine associations of self-reported smoking status and clinical outcomes, according to 90-day modified Rankin Scale (mRS) scores and symptomatic intracerebral haemorrhage (sICH). Results Of 4540 patients who had an AIS, there were 1008 (22.2%) current smokers who were younger and predominantly male, with more comorbidities of hypertension, coronary artery disease, atrial fibrillation and diabetes mellitus, and greater baseline neurological impairment, compared with non-smokers. In univariate analysis, current smokers had a higher likelihood of a favourable shift in mRS scores (OR 0.88, 95% CI 0.77 to 0.99; p=0.038) but this association reversed in a fully adjusted model with IPTW (adjusted OR 1.15, 95% CI 1.04 to 1.28; p=0.009). A similar trend was also apparent for dichotomised poor outcome (mRS scores 2-6: OR 1.18, 95% CI 1.05 to 1.33; p=0.007), but not with the risk of sICH across standard criteria. Conclusion Smoking predicts poor functional recovery in patients who had thrombolysed AIS. Trial registration number NCT01422616

Baseline brain imaging signs in patients with ischaemic stroke by the presence of atrial fibrillation: the ENCHANTED trial

Background: We aimed to assess the association of atrial fibrillation (AF) on outcomes in a post hoc analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) and how this association is modified by baseline imaging features. Methods: Inverse probability of treatment weight was used to remove baseline imbalances between those with and without AF. The primary outcome was the modified Rankin Scale (mRS) scores at 90 days. Secondary outcomes were symptomatic intracerebral haemorrhage (sICH), early neurological deterioration or death within 24 h, and death at 90 days. The logistic regression model was used to determine the associations. Results: Of the 3285 patients included in this analysis, 636 (19%) had AF at baseline. Compared with non-AF, AF was not significantly associated with an unfavourable shift of mRS (odds ratio 1.09; 95% confidence interval, 0.96–1.24), but with sICH (2.82; 1.78-4.48; IST-3 criteria), early neurological deterioration or death within 24 h (1.31; 1.01-1.70), and death (1.42; 1.12-1.79). Among patients with acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions), AF was associated with the increased risk of all the poor outcomes (all P < 0.04 for interaction). Conclusions: We found AF increased risk of sICH, early neurological deterioration or death and death, but not unfavourable functional recovery at day 90 after thrombolysis in patients with AIS. The presence of acute ischaemic brain imaging signs at stroke presentation could be used to improve risk stratification in the presence of AF. Trial registration: The trial is registered at ClinicalTrials.gov (NCT01422616)

Influence of renal function on blood pressure control and outcome in thrombolyzed patients after acute ischemic stroke: post-hoc analysis of the ENCHANTED trial

Background: The effect of renal impairment in patients who receive intravenous thrombolysis for acute ischemic stroke (AIS) is unclear. We aimed to determine the associations of renal impairment and clinical outcomes and any modification of the effect of intensive versus guideline-recommended blood pressure (BP) control in the BP arm of the International Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods: We conducted a post-hoc analysis of the ENCHANTED BP arm, which involved 2,196 thrombolyzed AIS patients. Logistic regression models were used to define the association between eGFR and clinical outcomes of death, death or major disability [modified Rankin scale (mRS) scores 3–6], and major disability (mRS 3–5) at 90 days. Results: Of the 2,151 patients with available baseline renal function data (mean age 66.9 years; 38% women), 993 (46.2%), 822 (38.2%), and 336 (15.6%) had normal (eGFR ≥ 90 mL/min/1.73 m2), mildly (60–89), and moderate-to-severely impaired (<60) renal function, respectively. Compared with patients with normal eGFR, mortality was higher in those with moderate-to-severe renal impairment (adjusted odds ratio 1.77, 95% confidence interval 1.05–2.99; p = 0.031 for trend). However, the difference in death or major disability (mRS 3–6) was not significant between groups. There was no heterogeneity in the effect of intensive versus guideline-recommended BP-lowering treatment on death by grades of renal function (p for interaction = 0.545). Discussion: The presence of moderate-to-severe renal impairment is associated with increased mortality in thrombolyzed patients with AIS. Renal function does not modify the effect of early intensive BP-lowering treatment on death in this patient group

The impact of frailty on the effectiveness and safety of intensive glucose control and blood pressure-lowering therapy for people with type 2 diabetes: Results from the ADVANCE trial

OBJECTIVE To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments