Novel Clot Buster Flops Again

So what is the next step  to solve this? Not doing anything is not okay, but that is what will happen since we have NO stroke leadership.
http://www.medpagetoday.com/cardiology/strokes/51760

Desmoteplase didn't help late-presenting strokes, the DIAS-3 trial shows.

• by Crystal Phend
  Senior Staff Writer, MedPage Today May 26, 2015
• This article is a collaboration between MedPage Today® and:
  

The investigational thrombolytic desmoteplase didn't improve reperfusion or outcomes compared with placebo in ischemic strokes treated 3 to 9 hours after onset, the DIAS-3 trial showed.
A good functionally independent outcome, marked by a modified Rankin Scale score of 0 to 2, at 90 days occurred in 51% of desmoteplase-treated patients compared with 50% given placebo (P=0.40), Gregory W. Albers, MD, of the Stanford School of Medicine in Stanford, Calif., and colleagues found.
Recanalization at 24 hours, monitored with noninvasive imaging, likewise came out similar between treatment groups (49% and 42%, respectively), they reported in the June issue of Lancet Neurology.
"This factor is key in the neutral results and raises questions about the thrombolytic efficiency of desmoteplase in late time windows," Michael D. Hill, MD, and Bijoy K. Menon, MD, both of the University of Calgary Stroke Program in Alberta, wrote in an accompanying editorial.

The prior phase III DIAS-2 trial with the drug, which is based on the saliva of the vampire bat, had also turned out negative using a different imaging-based selection scheme for enrollment.

DIAS-3 used a "simpler imaging selection paradigm: small core (less than a third of the middle cerebral artery [MCA] or less than a half of the anterior cerebral artery [ACA] or posterior cerebral artery [PCA] territories), plus evidence of a target intracranial arterial occlusion," Hill and Menon noted.
However, imaging protocol violations were common in the trial, with imaging discrepancies in 21% of the 292 acute ischemic stroke patients with occlusion or high-grade stenosis in major cerebral arteries treated at a median 7 hours after onset.
Although serious adverse events, including intracerebral hemorrhage and symptomatic cerebral edema, were similar between groups, another phase III trial, DIAS-4, was stopped based on early indications of futility in DIAS-3.
The researchers pointed to a possible benefit of desmoteplase in small ischemic lesions selected by MRI that might be worth further study.
While that group might have been less prone to imaging measurement error, "this finding would have been more meaningful if increased recanalization early after administration of the thrombolytic agent was also shown in the small core group," the editorialists cautioned.
It may be that late-presenting, small core strokes are just not a good population to target, they suggested.
"We speculate that patients who arrive late without having a large, established core of infarction shown in imaging are more likely to have preserved penumbral tissue because of good intracranial collateral circulation," Hill and Menon wrote. "Such patients could stand to benefit less from thrombolysis, even with reperfusion.
"Further, with time, thrombi mature and fibrin cross-links, resulting in resistance to thrombolysis. Patients who present in later time windows might simply be less amenable to chemical thrombolysis."

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke

Whom is going to plan and execute followup research that will find and significantly improve functional outcome at 3 months?  A great stroke association would handily do this. I blame our boards of directors for allowing promising research to languish forever.
http://stroke.ahajournals.org/content/47/12/2880.abstract?etoc
http://dx.doi.org/10.1161/STROKEAHA.116.013715

Stroke. 2016;47:2880-2887

Originally published November 1, 2016

Abstract

Background and Purpose—The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window.

Methods—Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events.

Results—In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08–2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0–2) at day 90 in both the treatment arms.

Conclusions—Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Stroke Rounds: Novel Clot Buster Flops Again - desmoteplase

I guess vampire bat saliva doesn't work that well. I would argue that the Rankin scale used to evaluate effectiveness is totally inappropriate. If you want to do this objectively you run daily MRI scans to see if the size of the dead area increases less with interventions vs. placebo. Still to be tested;
1. liposome-encapsulated hemoglobin written in Feb. 2010
2. bat saliva - Draculin  written in May, 2011, up to 9 hours OK, maybe a no go
3. cardiac glycosides written in Feb. 2006 - up to 6 hours
4.inhalation of nitric oxide written in March, 2012 - 48 hours to 7 days
5. Nitric oxide written in 2006, to be tested in humans yet.
6. xenon gas written in Feb. 2006, to be tested yet
7. caffeinol irish coffee injection written in April 2003 to be tested in humans
8. Docosahexaenoic acid (DHA), a component of fish oil written in Nov. 2010, up to 5 hours
9. nicotine written in July 2005, to be tested in humans
10. Viagra written in 2002, to be tested in humans,  for 7 days
11.
11. Enzogenol  written in Nov. 2011 for New Zealand
12 edaravone approved in Japan since 2001
13. nitroglycerin instructions
14. benzodiazepine inverse agonist  written in Nov. 2010 

http://www.medpagetoday.com/Cardiology/Strokes/51760?xid=nl_mpt_DHE_2015-05-27&eun=g424561d0r

Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly

What does your doctor think of this?
Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly

Abstract

Stroke is a major cause of both death and disability. However, there are no pharmacological treatments used in most countries other than recombinant tissue plasminogen activator, a thrombolytic, and this is only used in about 4% of patients presenting after an acute ischaemic stroke. One novel thrombolytic (desmoteplase) has just been reported to have failed in a Phase IIb/III trial, but other thrombolytics and reperfusion agents remain in development. The picture with neuroprotectant agents, that is compounds that act to preserve neurones following an acute cerebral ischaemic insult, is even more bleak. Despite the development of over 1000 compounds, many proving effective in animal models of stroke, none has demonstrated efficacy in patients in the over 100 clinical trials conducted. This includes NXY-059, which was developed in accordance with the guidelines proposed by an academic-industry roundtable group (STAIR). This review examines the available data on compounds currently in development. It also proposes that the failure of translation between efficacy in preclinical models and patients is likely to terminate most current neuroprotective drug development. It is suggested that animal models must be made more representative of the patient condition (with other co-morbid conditions) and suggests that since stroke is primarily a cardiovascular disease with a neurological outcome, more research on the neurovascular unit would be valuable. New approaches on neuroinflammation, neurorestoration and neurorepair are also likely to gain prominence in the search for new drugs to treat this major clinical problem.