Estimating risk when zero events have been observed

Assessing the risk of complications or adverse events following an intervention presents challenges when they have not yet occurred. Suppose, for instance, a chronic shortage of cardiac telemetry beds has prompted a hospital to implement a new policy that places low-risk patients admitted to ‘rule out myocardial infarction’ in regular ward beds (ie, with no telemetry). After 6 months and the admission of 100 such patients, no cardiac arrests or other untoward events have occurred. This absence of harm (ie, zero adverse events) indicates a low risk, but clearly we cannot infer a risk of zero on the basis of only 100 patients. But, what can we say about the true underlying risk

Prevention of stroke: risk stratification and targeted and novel therapies

Stroke is a common disorder with dire consequences for the patient and for society and will increase in prevalence over the coming years. Following stroke, many patients unfortunately suffer a further stroke, and recurrent strokes account for approximately 25% of the total. Considerable scope therefore exists to improve both primary and secondary stroke prevention. This thesis has addressed several areas at key stages in the prevention of stroke by developing strategies to better identify those at highest risk, attempting to better target pre-existing anti-platelet therapy and by beginning the evaluation of xanthine oxidase reduction and uric acid lowering therapy in the prevention of stroke. A clinical scoring system to aid diagnostic recognition in those with suspected transient ischaemic attack (TIA) was successfully developed and has the ability to reduce the referral of those without cerebrovascular disease to busy TIA clinics. The score was developed on data from 3216 patients and included 9 clinically useful predictive variables. After adjustment to reflect the greater seriousness of missing true TIA patients, 97% of TIA and 22% of non-TIA patients were accurately identified. The results were confirmed during prospective validation. Use of the score could have a substantial effect on waiting times for assessment; there is potential double the numbers seen within the timeframe recommended by guidelines with no other change to services. This would be an important advance given the recent evidence that rapid assessment and treatment of those with TIA greatly reduces stroke risk. Aspirin resistance was found to be higher in those with cerebrovascular microembolic signals (MES) and carotid disease compared to those with equivalent carotid disease and no MES. This study included sixty-two patients who mostly had symptomatic carotid disease. Approximately a quarter had MES. The rate of aspirin resistance on at least one test was 25.8% (16 patients), with 13 (21%) resistant on PFA-100 testing, 8 (12.9%) using the Verify-Now system and 5 (8.1%) resistant on both. Aspirin resistance was more common in patients with MES (50% compared to 17.4% without, p=0.018 on Fishers exact test). This provides a link to a well established and robust surrogate marker of outcome and thus a useful model to further study the benefits of guided anti-platelet strategies. An interventional clinical anti-platelet trial based upon individual aspirin responsiveness in high risk individuals such as those with MES is now warranted. Aspirin resistance was also confirmed to be a common phenomenon in a case-control study of 180 patients. It was present in 34% of those with recent stroke and in 18% of those with risk factors but no established disease. However, the role of poor compliance with therapy as a cause in a substantial number of cases was established; it accounted for approximately half of those labelled resistant in the stroke group. Further, when only those with objective evidence of recent aspirin ingestion were considered, the prevalence of aspirin resistance was similar in both groups (at 26%). This suggests that objective measures to confirm compliance with aspirin therapy should be mandatory in future studies of aspirin resistance. Increasing serum uric acid was found to be a predictor of poor functional outcome following acute stroke but not in an independent fashion. In total, 852 patients were included in this study and greater uric acid levels were associated with increased odds of poor outcome on univariate but not multivariate analysis (OR 1.3, 95% CI 0.73-2.31). However, there was no evidence of an association with favourable outcome as other groups have found. Increasing serum uric acid was also shown to be predictive of increased risk of stroke, total, vascular and coronary mortality in treated hypertensive patients but interestingly, the relationship between stroke mortality and serum uric acid appears J-shaped and most apparent in females. A study of the use of allopurinol in those with diabetes showed that xanthine oxidase inhibition improves cerebral nitric oxide bioavailability suggesting a beneficial effect of allopurinol on cerebrovascular health. This study included 14 participants who had impaired baseline cerebrovascular nitric oxide bioavailability. Allopurinol led to a significant improvement in responses to NG-monomethyl-L-arginine (L-NMMA) when compared to placebo (p=0.032, median improvement in ICA flow reduction following L-NMMA of 3144 (95% CI 375 to 7143)) mls). L-NMMA is an inhibitor of endothelial nitric oxide synthase which reduces cerebral blood flow in healthy volunteers; the bigger the reduction, the greater the endothelial health. However, a study of the effect of allopurinol treatment on cerebrovascular reactivity (as measured by response to acetazolamide infusion) in a group of patients with recent subcortical stroke revealed no positive effect. Cerebrovascular reactivity was unchanged by treatment with allopurinol. This raises interesting questions regarding the longevity of any positive effect of allopurinol as this, and other studies of 3 month duration, have revealed no benefit. Further, subjects in this study did not, on balance, have elevated serum uric acid and it has recently been suggested that only those with significantly elevated levels benefit in the setting of congestive cardiac failure. Whether this is also true in those with stroke also requires to be clarified. A large study of the effect of allopurinol on carotid intima-media thickness, a robust and modifiable marker of vascular risk, in those with recent stroke is planned to address these questions. The studies in this thesis therefore include a number of pragmatic findings which could improve care at all stages in the prevention of stroke. The TIA scoring system could improve recognition of the high risk condition TIA, a useful model has been developed in which to study a population of patients truly resistant to aspirin and important lessons have been learned to aid further evaluation of xanthine oxidase inhibition; a promising therapy for the prevention of stroke

Cessation of dual antiplatelet therapy and cardiovascular events following acute coronary syndrome

Objective: To assess whether cardiovascular events are increased after cessation of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) and to explore predictors for recurrent events after DAPT cessation during long-term follow-up. Methods: We did a retrospective observational cohort study. We included consecutive people with ACS who were discharged from Scottish hospitals between January 2008 and December 2013 and who received DAPT after discharge followed by antiplatelet monotherapy. The rates of cardiovascular events were assessed during each 90-day period of DAPT treatment and 90-day period after stopping DAPT. Cardiovascular events were defined as a composite of death, ACS, transient ischaemic attack or stroke. Cox regression was used to identify predictors of cardiovascular events following DAPT cessation. Results: 1340 patients were included (62% male, mean age 64.9 (13.0) years). Cardiovascular events occurred in 15.7% (n=211) during the DAPT period (mean DAPT duration 175.1 (155.3) days) and in 16.7% (n=188) following DAPT cessation (mean of 2.7 years follow-up). Independent predictors for a cardiovascular event following DAPT cessation were age (HR 1.07; 95% CI 1.05 to 1.08; p<0.001), DAPT duration (HR 0.997; 95% CI 0.995 to 0.998; p<0.001) and having revascularisation therapy during the index admission (HR 0.58; 95% CI 0.39 to 0.85; p=0.005). Conclusions: The rate of cardiovascular events was not significantly increased in the early period post-DAPT cessation compared with later periods in this ACS population. Increasing age, DAPT duration and lack of revascularisation therapy were associated with increased risk of cardiovascular events during long-term follow-up after DAPT cessation

Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient

Background: Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitation can enhance neural plasticity in the primary sensory and motor cortices, improve forelimb function after stroke in animal models and improve motor function in patients with arm weakness after stroke. OBJECTIVE:To gain “first-in-man” experience of VNS paired with tactile training in a patient with severe sensory impairment after stroke. Methods: During the long-term follow-up phase of a clinical trial of VNS paired with motor rehabilitation, a 71-year-old man who had made good motor recovery had ongoing severe sensory loss in his left hand and arm. He received VNS paired with tactile therapy in an attempt to improve his sensory function. During twenty 2-hour sessions, each passive and active tactile event was paired with a 0.5 second burst of 0.8 mA VNS. Sensory function was measured before, halfway through, and after this therapy. Results: The patient did not report any side effects during or following VNS+Tactile therapy. Quantitative measures revealed lasting and clinically meaningful improvements in tactile threshold, proprioception, and stereognosis. After VNS+Tactile therapy, the patient was able to detect tactile stimulation to his affected hand that was eight times less intense, identify the joint position of his fingers in the affected hand three times more often, and identify everyday objects using his affected hand seven times more often, compared to baseline. Conclusions: Sensory function significantly improved in this man following VNS paired with tactile stimulation. This approach merits further study in controlled clinical trials

Chicken or the egg? Hyperuricemia, insulin resistance, and hypertension

No abstract available

Functional assessment for acute stroke trials: properties, analysis, and application

A measure of treatment effect is needed to assess the utility of any novel intervention in acute stroke. For a potentially disabling condition such as stroke, outcomes of interest should include some measure of functional recovery. There are many functional outcome assessments that can be used after stroke. In this narrative review, we discuss exemplars of assessments that describe impairment, activity, participation, and quality of life. We will consider the psychometric properties of assessment scales in the context of stroke trials, focusing on validity, reliability, responsiveness, and feasibility. We will consider approaches to the analysis of functional outcome measures, including novel statistical approaches. Finally, we will discuss how advances in audiovisual and information technology could further improve outcome assessment in trials

Multimodal interventions to enhance adherence to secondary preventive medication after stroke: a systematic review and meta-analyses

Summary: Introduction: Nonadherence to secondary preventative medications after stroke is common and is associated with poor outcomes. Numerous strategies exist to promote adherence. We performed a systematic review and meta-analysis to describe the efficacy of strategies to improve adherence to stroke secondary prevention. Methods: We created a sensitive search strategy and searched multiple electronic databases (MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL, and Web of Knowledge) for studies of interventions that aimed to enhance adherence to secondary preventative medication after stroke. We assessed quality of included studies using the Cochrane tool for assessing risk of bias. We performed narrative review and performed meta-analysis where data allowed. Results: From 12,237 titles, we included seventeen studies in our review. Eleven studies were considered to have high risk of bias, 3 with unclear risk, and 3 of low risk. Meta-analysis of available data suggested that these interventions improved adherence to individual medication classes (blood pressure-lowering drugs – OR, 2.21; 95% CI (1.63, 2.98), [P < 0.001], lipid-lowering drugs – OR, 2.11; 95% CI (1.00, 4.46), [P = 0.049], and antithrombotic drugs – OR, 2.32; 95% CI (1.18, 4.56, [P = 0.014]) but did not improve adherence to an overall secondary preventative medication regimen (OR, 1.96; 95% CI (0.50, 7.67), [P = 0.332]). Conclusion: Interventions can lead to improvement in adherence to secondary preventative medication after stroke. However, existing data is limited as several interventions, duration of follow-up, and various definitions were used. These findings need to be interpreted with caution

The Potential for Xanthine Oxidase Inhibition in the Prevention and Treatment of Cardiovascular and Cerebrovascular Disease

There is a now a wealth of epidemiological, animal, and clinical data to suggest the benefits of uric acid reduction and hxanthine oxidase inhibition in prevention of vascular disease. This review discusses the available epidemiological, preclinical, and clinical data and considers arguments for and against a role for serum uric acid in common cardiovascular disorders. It concludes that large scale trials with clinical endpoints are justified to address this important question and to define whether use of drugs such as allopurinol should be a routine part of preventative strategies

Acute stroke: we have the treatments and we have the evidence – we need to use them

Despite huge global burden, stroke disease has traditionally received little attention in the general medical press. We review a series of four acute stroke research articles published in a themed issue of the Lancet. Claiborne-Johnston and coworkers presented a scoring system to stratify risk of stroke following transient ischaemic attack. Chalela and colleagues demonstrated that magnetic resonance imaging is superior to computed tomography in detecting acute ischaemic stroke and that fears of missing intracranial haemorrhage are unfounded. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke – Monitoring Study) group reported positive experience of translating acute stroke thrombolysis trials into routine clinical practice in Europe, and the PROSIT (Project on Stroke Services in Italy) group studied acute effects of admission to a dedicated stroke unit. The message from all of these reports is that evidence-based, successful management of acute stroke is possible, and that investment in health infrastructure and changing mind sets of health practitioners to improve stroke care will deliver benefits

Renal replacement modality and stroke risk in end-stage renal disease—a national registry study

Background: The risk of stroke in end-stage renal disease (ESRD) on renal replacement therapy (RRT) is up to 10-fold greater than the general population. However, whether this increased risk differs by RRT modality is unclear. Methods: We used data contained in the Scottish Renal Registry and the Scottish Stroke Care Audit to identify stroke in all adult patients who commenced RRT for ESRD from 2005 to 2013. Incidence rate was calculated and regression analyses were performed to identify variables associated with stroke. We explored the effect of RRT modality at initiation and cumulative dialysis exposure by time-dependent regression analysis, using transplant recipients as the reference group. Results: A total of 4957 patients commenced RRT for ESRD. Median age was 64.5 years, 41.5% were female and 277 patients suffered a stroke (incidence rate was 18.6/1000 patient-years). Patients who had stroke were older, had higher blood pressure and were more likely to be female and have diabetes. On multivariable regression older age, female sex, diabetes and higher serum phosphate were associated with risk of stroke. RRT modality at initiation was not. On time-dependent analysis, haemodialysis (HD) exposure was independently associated with increased risk of stroke. Conclusions: In patients with ESRD who initiate RRT, HD use independently increases risk of stroke compared with transplantation. Use of peritoneal dialysis did not increase risk on adjusted analysis