The Hazard of Negative (Not Neutral) Trials on Treatment of Acute Stroke

Abstract

cute stroke has multiple treatment interventions, including strokeunitsforallpatients 1 ;reperfusiontherapies(eg,thrombolysis, thrombectomy), 2-4 aspirin, 5 and hemicraniectomy 6 for acute ischemic stroke; and blood pressure (BP) lowering for hyperacute hemorrhagic stroke. 7 In contrast, other classes of interventions have failed to show efficacy, notably anticoagulation, neuroprotection, and BP lowering for acute ischemic stroke. Although most acute stroke randomized clinical trials (RCTs) have neutral findings (ie, the intervention did not show a significant effect on its primary outcome), a significant proportion have negative outcomes, with the intervention apparently being hazardous. It is inevitable that trials with negative findings will exist; the uncertainty principle that should underpin all RCTs means that although we start with a plausible and defendable idea, unknown factors may lead to a trial having neutral or negative findings. Nevertheless, the number of RCTs with negative outcomes could be limited through improved preclinical study design, delivery, and clinical oversight during trials. By examining acute stroke RCTs with negative outcomes,thesubjectofthisreview,wehopefullycanreducetheirnumber. MethodsIn this review, negative is used in the broad sense that the experimental treatment was associated with 1 or more statistically nega-tive clinical outcomes, whether or not these included the primary outcome. Hence, the intervention may have been associated with more impairment, disability, dependency, death, or serious adverse events (SAEs). In some cases, data monitoring committees (DMCs) or sponsors stopped trials early for hazard on the basis of interim analysis, in which case the relevant outcome may not still be negative once all final outcomes have been collected. Where trials studied 2 or more doses, hazard was more likely to be present at the highest dose, and the following comments tend to relate to this dose.The negative trials referenced here are those known to the authors through their own libraries of references. 8,9 A formal systematic search was not performed, largely because many authors refer to trials with neutral findings as being negative (ie, not positive), which massively reduces the specificity of any electronic search. The distinction between neutral and negative is important both to explain trial results and to assess potential reasons, and the common verbal and written use of negative to mean not positive should be resisted. Interventions cover drugs, biologics, cells, and devices. The review does not cover the large number of acute stroke RCTs with neutral findings and an explanation for these, but often, neutral findings reflect lack of efficacy or small sample size. No tabulated data or statistical analyses were performed.IMPORTANCE While there are a limited number of beneficial treatments for acute stroke (eg, stroke units, reperfusion, aspirin, hemicraniectomy), there are more negative (as opposed to neutral) interventions spanning multiple different mechanisms of act...

Key design elements of successful acute ischemic stroke treatment trials

“…To the best of our ability, over the past 25 years, we were only able to identify 17 positive acute stroke trials With 888 interventional acute stroke trials registered in this period, the success rate is extremely low [ 50 ]; indeed there are more negative (not neutral) trials and interventions [ 3 ]. Successful trials share similarities in their design, most were investigator-initiated, publicly-funded, recruited nationally or regionally, and selected patients based on strict time, stroke severity, or imaging criteria.…”

“…Hundreds of candidate drugs have been tested in stroke models in rats, mice, canines and primates, many of them yielding smaller infarcts in treated animals. However, the positive effects were not confirmed in subsequent multicenter phase 2 and 3 clinical trials [ 3 ]. Reasons for the translation failure include: the use of inappropriate animal models (young, male animals), experiments which do not mimic clinical practice (e.g., treatment prior to vessel occlusion), use of different dosages, unexpected adverse events, overestimation of effect sizes leading to underpowered trials and wide eligibility criteria with inclusion of non-informative patients [ 4 ].…”

“…Trials were considered 'positive' if they met the following criteria: (1) a randomized controlled design, with (at least partial) blinding for endpoints, (2) tested against placebo (or on top of standard therapy in a superiority design) or against approved therapy (such as rtPA); (3) protocol was registered and/or published before trial termination and unblinding (if required at study commencement); (4) primary endpoint was positive in the intention to treat analysis; and (5) the study findings led to approval of the investigational product and/or high ranked recommendations in internationally accepted guidelines.…”

Evolution of Evidence-Based Medicine in Stroke

“…Between the mid-1980s and mid-2000s, many positive results in pre-clinical studies of stroke therapies failed to translate to positive results in large clinical RCTs, and some therapies were even harmful [80,81]. Reasons included poor pre-clinical experimental design, conduct, delivery, and clinical oversight.…”

Characterization of a novel model of global forebrain ischaemia–reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke

“…As a corollary, in primary ICH cases, protecting endothelial cells, astrocytes and pericytes might reduce haematoma expansion and oedema. Characterising BBB breakdown and oedema as well as bleeding in the brain is further valid during development of new antiplatelet, anticoagulant, or fibrinolytic therapies for ischaemic stroke, to test haemorrhagic transformation of an ischaemia-induced infarct 7 .…”