Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

Publication bias confounds attempts to use systematic reviews to assess the efficacy of various interventions tested in experiments modelling acute ischaemic stroke, leading to a 30% overstatement of efficacy of interventions tested in animals.

The consolidation of scientific knowledge proceeds through the interpretation and then distillation of data presented in research reports, first in review articles and then in textbooks and undergraduate courses, until truths become accepted as such both amongst “experts” and in the public understanding. Where data are collected but remain unpublished, they cannot contribute to this distillation of knowledge. If these unpublished data differ substantially from published work, conclusions may not reflect adequately the underlying biological effects being described. The existence and any impact of such “publication bias” in the laboratory sciences have not been described. Using the CAMARADES (Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Studies) database we identified 16 systematic reviews of interventions tested in animal studies of acute ischaemic stroke involving 525 unique publications. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report at least one significant finding. Egger regression and trim-and-fill analysis suggested that publication bias was highly prevalent (present in the literature for 16 and ten interventions, respectively) in animal studies modelling stroke. Trim-and-fill analysis suggested that publication bias might account for around one-third of the efficacy reported in systematic reviews, with reported efficacy falling from 31.3% to 23.8% after adjustment for publication bias. We estimate that a further 214 experiments (in addition to the 1,359 identified through rigorous systematic review; non publication rate 14%) have been conducted but not reported. It is probable that publication bias has an important impact in other animal disease models, and more broadly in the life sciences.

Author Summary

Publication bias is known to be a major problem in the reporting of clinical trials, but its impact in basic research has not previously been quantified. Here we show that publication bias is prevalent in reports of laboratory-based research in animal models of stroke, such that data from as many as one in seven experiments remain unpublished. The result of this bias is that systematic reviews of the published results of interventions in animal models of stroke overstate their efficacy by around one third. Nonpublication of data raises ethical concerns, first because the animals used have not contributed to the sum of human knowledge, and second because participants in clinical trials may be put at unnecessary risk if efficacy in animals has been overstated. It is unlikely that this publication bias in the basic sciences is restricted to the area we have studied, the preclinical modelling of the efficacy of candidate drugs for stroke. A related article in PLoS Medicine (van der Worp et al., doi:10.1371/journal.pmed.1000245) discusses the controversies and possibilities of translating the results of animal experiments into human clinical trials.

Background

Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.

Methodology/Principal Findings

A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01).

Conclusions/Significance

Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy.

Trial Registration

Controlled-Trials.com ISRCTN83673558

Aims

Randomized controlled trials (RCTs) have shown that the risk of stroke and venous thromboembolism (VTE) is increased with hormone replacement therapy (HRT); the effect on coronary heart disease (CHD) remains unclear.

Methods and results

RCTs of HRT were identified. Event rates for cerebrovascular disease [stroke, TIA (transient ischaemic attack)], CHD (myocardial infarction, unstable angina, sudden cardiac death), and VTE (pulmonary embolism, deep vein thrombosis) were analysed. Sensitivity analyses were performed by type of HRT (mono vs. dual) and subject age. 31 trials (44 113 subjects) were identified. HRT was associated with increases in stroke (odds ratio, OR, 1.32, 95% confidence intervals, CI, 1.14–1.53) and VTE (OR 2.05, 95% CI 1.44–2.92). In contrast, CHD events were not increased (OR 1.02, 95% CI 0.90–1.11). Ordinal analyses confirmed that stroke severity was increased with HRT (OR 1.31, 95% CI 1.12–1.54). Although most trials included older subjects, age did not significantly affect risk. The addition of progesterone to oestrogen doubled the risk of VTE.

Conclusion

HRT is associated with an increased risk of stroke, stroke severity, and VTE, but not of CHD events. Although most trials studied older patients, increased risk was not related to age. Combined HRT increases the risk of VTE compared with oestrogen monotherapy.

Objectives To review completed trials assessing effect of hormone replacement therapy on subsequent risk of stroke, assessing stroke by pathological type, severity, and outcome.

Design Systematic review of randomised controlled trials identified from the Cochrane Library, Embase, and Medline; reviews; and reference lists of relevant papers.

Studies reviewed 28 trials, with 39 769 subjects, were identified.

Review measures Rates for cerebrovascular events analysed with a random effects model. Sensitivity analyses for heterogeneity included phase of prevention (primary or secondary), type of hormone replacement therapy (oestrogen alone or combined with progesterone), type of oestrogen (estradiol or conjugated equine oestrogen), size of trial (< 5000 or > 5000 patients), length of follow up (£ 3 years or > 3 years), sex (women only or men only), and trial quality (high or low).

Results Hormone replacement therapy was associated with significant increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to 1.47), n = 28), non-fatal stroke (1.23 (1.06 to 1.44), n = 21), stroke leading to death or disability (1.56 (1.11 to 2.20), n = 14), ischaemic stroke (1.29 (1.06 to 1.56), n = 16), and a trend to more fatal stroke (1.28 (0.87 to 1.88), n = 22). It was not associated with haemorrhagic stroke (1.07 (0.65 to 1.75), n = 17) or transient ischaemic attack (1.02 (0.78 to 1.34), n = 22). Statistical heterogeneity was not present in any analysis.

Conclusions Hormone replacement therapy was associated with an increased risk of stroke, particularly of ischaemic type. Among subjects who had a stroke, those taking hormone replacement therapy seemed to have a worse outcome. Hormone replacement therapy cannot be recommended for the primary or secondary prevention of stroke.