Adding anti-clotting drugs to stroke care ineffective, clinical trial finds

 I must be missing something, neither of these drugs could help recovery, shouldn't the endpoint have been, preventing another stroke?

Adding anti-clotting drugs to stroke care ineffective, clinical trial finds

Medications thought to show promise did not improve patients’ outcomes

Peer-Reviewed Publication

Washington University School of Medicine

image: 

Opeolu Adeoye, MD,  and Peter Panagos, MD, (right) both professors of emergency medicine at Washington University School of Medicine in St. Louis, analyze a brain scan for stroke damage. Adeoye led a national clinical trial  that found that two anti-coagulant medications are ineffective at improving post-treatment outcomes for stroke patients.

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Credit: Tim Miller

Stroke patients who survive a blood clot in the brain’s blood vessels are prone to developing new blockages during their recovery periods, even if they receive vessel-clearing interventions. In an effort to avoid further clots, doctors at 57 sites around the U.S. tested a possible solution: the addition of anti-coagulant drugs to medicine that dissolves blood clots.

But results from the clinical trial, led by Opeolu Adeoye, MD, head of the Department of Emergency Medicine at Washington University School of Medicine in St. Louis, indicate two such drugs did not improve outcomes.

The findings are available Sept. 4 in The New England Journal of Medicine.

“We’re a little disappointed in the results,” said Adeoye, who is also the BJC HealthCare Distinguished Professor of Emergency Medicine. “But it’s meaningful to optimal patient care that we’ve answered the question definitively. Neither of the drugs helps prevent further clots.”

The goal of the Multi-arm Optimization of Stroke Thrombolysis (MOST) clinical trial that Adeoye led was to test the efficacy of adding argatroban, a blood thinner, or eptifibatide, which inhibits blood platelets from sticking together, to the routine intravenous thrombolysis treatment.

The trial closed the chapter on this potential use of these medications, but Peter Panagos, MD, professor of emergency medicine and co-author on the study, said that efforts like these inform future advances in medicine, including potential new anti-coagulant treatments.

“Without negative trials, we would not know how to design new trials,” Panagos said. “Future success is built upon the hard work of previous research effort.”

Physicians do not have a lot of treatment options for patients who experience a stroke. Some patients undergo a procedure to remove the clot. Others receive intravenous thrombolysis to relieve the affected blood vessel through clot-dissolving medication delivered to the bloodstream. A number of patients receive both interventions.

“Even with those treatments, over half of patients still have a significant disability three months after their stroke," said Adeoye, who treats patients at Barnes-Jewish Hospital and Missouri Baptist Medical Center and also provides stroke telemedicine consultation. "After you give the thrombolysis, the clot can re-form, which contributes to the stroke worsening or persisting.”

Preventing these clots with an additional treatment of anti-coagulant drugs seemed like a promising idea, especially as there are FDA-approved medications that earlier studies had suggested could be effective.

In the MOST trial, patients were randomly assigned to receive either argatroban, eptifibatide or placebo. Adeoye explained that the study had checkpoints built in to ensure that treatment outcomes were meeting efficacy thresholds in order to continue. The first checkpoint was set at 500 patients, which the team reached in 2023.

“When we looked at the data, it was readily apparent that neither drug was going to come anywhere close to our threshold,” he said.

In fact, the probability that either drug was helpful was less than 1%. Worse still, argatroban and eptifibatide were linked to greater incidences of disability and mortality within the three-month post-treatment observation window.

This correlation was not necessarily alarming; the safety monitors on the project found that the deaths appeared to have causes unrelated to the medications. The lack of improvement noted with the medications compared with what was noted with the placebo was reason enough to call off the trial.

There are more options to pursue in seeking to improve stroke outcomes. Adeoye said there are drugs in development that target different parts of the blood coagulating and clotting processes that may prove to be more effective than argatroban or eptifibatide, and other procedures such as direct arterial delivery through which such drugs might be more effective.

Panagos, who directs the new Section of Neurologic Emergencies in the Department of Emergency Medicine, added that WashU Medicine’s leadership in trials such as this one benefits the 1,700 stroke patients who are treated by WashU Medicine physicians at Barnes-Jewish Hospital every year.

“Because we are involved in and lead most of the key basic science and clinical research for stroke and cerebrovascular patients nationally and internationally, we can bring the latest interventions to our patients in St. Louis and help advance treatment and prevention strategies,” Panagos said. “Our involvement in clinical trials helps bring the highest quality, most innovative treatments to our community.”

Adeoye O, Broderick J, Derdeyn CP, Grotta JC, Barsan W, Bentho O, Berry S., Concha M, Davis I, Demel S, Elm J, Gentile N, Graves T, Hoffman M, Huang J, Ingles J, Janis S, Jasne AS, Khatri P, Levine SR, Majjhoo A, Pancioli A, Panagos P, Pizzella S, Ranasinghe T, Sabagha N, Sivakumar S, Streib C, Vagal A, Wilson A, Wintermark M, Yoo AJ, Barreto AD. Adjunctive intravenous argatroban or eptifibatide for ischemic stroke. The New England Journal of Medicine. Sept. 4, 2024.

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Journal

New England Journal of Medicine

Direct Thrombin Inhibitor Shows Benefit for Progressing Stroke

WHOM in your hospital is following this research so when totally proven it gets implemented? Or don't you have a functioning stroke hospital because there is no research analyst whose only job is to follow and implement stroke research?And they call themselves a stroke hospital when not having that research analyst is TOTAL FUCKING INCOMPETENCY!

Finally someone realizing how poorly tPA does. And studies from 2004 recommended more testing. God, how slow are we?
The 1995 research here: Only 29 years later, still nothing new
Thrombin inhibition in the acute phase of ischaemic stroke using argatroban
The 2004 research here:
Argatroban Anticoagulation in Patients With Acute Ischemic Stroke (ARGIS-1)
The 2012 one here:
Further argatroban study ‘warranted’ in acute stroke

The latest here:

Direct Thrombin Inhibitor Shows Benefit for Progressing Stroke

Urgent anticoagulation with argatroban shows no bleeding downside in EASE trial

by Nicole Lou, Senior Staff Writer, MedPage Today January 9, 2024

Argatroban could revive the practice of acute anticoagulation for reducing disability after stroke, based on the EASE trial from China.

In patients with acute ischemic stroke and early neurological deterioration, urgent application of the direct thrombin inhibitor increased a person's likelihood of a good functional outcome (modified Rankin Scale score 0-3) at 90 days compared with usual care (80.5% vs 73.3%; RR 1.10, 95% CI 1.01-1.20).

This would appear to counter the evidence accumulated over the years showing that parenteral anticoagulation, typically IV heparin, has not been as beneficial in acute progressing stroke as believed decades ago.

Importantly, argatroban's efficacy did not come at the cost of excess bleeding, with rates of symptomatic intracranial hemorrhage (SICH) comparable between groups (0.9% vs 0.7%, P=0.78), reported Min Lou, MD, PhD, of the Second Affiliated Hospital, Zhejiang University School of Medicine in Hangzhou, and colleagues in JAMA Neurologyopens in a new tab or window.

"No harmful profile of argatroban was observed even in patients who received intravenous alteplase, suggesting the possible safety of anticoagulants," the EASE investigators wrote.

The trial selected progressing stroke patients who had an increase of 2 or more points on the NIH Stroke Scaleopens in a new tab or window within 48 hours from symptom onset. Participants were randomized 1:1 within 48 hours to standard therapy with or without argatroban. The argatroban group received IV argatroban at a continuous infusion of 60 mg per day for 2 days, followed by 20 mg per day for 5 days, whereas controls received standard therapy such as antiplatelets.

The relatively low dose of argatroban in EASE "may explain the low rates of bleeding observed," suggested Brett Cucchiara, MD, of the University of Pennsylvania in Philadelphia, and Jennifer Majersik, MD, of University of Utah in Salt Lake City, in an accompanying editorialopens in a new tab or window.

The pair cited the higher dose of argatroban tested in the ARAISopens in a new tab or window trial, in which the agent failed to better neurologic function over alteplase alone and was associated with excess SICH to boot.

"Many questions remain" and "these new data will undoubtedly fan the flames of the age-old controversy over if and when patients with acute stroke should be treated with parenteral anticoagulation," according to Cucchiara and Majersik.

"Combining antiplatelet therapy with low-dose anticoagulation has demonstrated efficacy for reducing vascular events, particularly stroke, in patients with chronic atherosclerotic disease. Given the EASE trial results, should this same strategy be tested more extensively in acute stroke?" they posed. "If low-dose acute anticoagulation combined with antiplatelet therapy is effective in patients with early deterioration, would it be even more effective if targeted at patients at high risk of deterioration before they worsen?"

Lou and colleagues also noted that the ideal timing of anticoagulation therapy after early neurological deterioration remains to be determined in future studies. Results also need to be confirmed in non-Chinese populations.

EASE was an open-label trial conducted in 28 Chinese sites. The 628 stroke patients averaged age 65 and 63.7% were men.

Study authors acknowledged that 98% of the argatroban group underwent the complete procedure of argatroban at a median 24 hours from symptom onset to randomization, whereas among controls, 89.8% were treated appropriately according to study protocol.

Nevertheless, per-protocol results were similar to those from the full analysis, Lou's group maintained.

The authors reported that while the control group was more likely to get dual antiplatelet therapy, this did not change the primary outcome. "Even with more application of dual antiplatelet therapy, the control group had less good functional outcome than the argatroban group, which may indicate the potential effect of argatroban."

"However, our study was neither powered nor specifically targeted at this treatment effect, and the results should therefore be interpreted with great caution," they stated.

• 

  Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

Disclosures

The trial was funded by grants from the National Natural Science Foundation of China.

Lou and Cucchiara had no disclosures.

Majersik reported grants from the NIH as well as personal fees from the American Heart Association, Woolsey Pharmaceuticals, and UpToDate.

Primary Source

JAMA Neurology

Source Reference: opens in a new tab or windowZhang X, et al "Argatroban in patients with acute ischemic stroke with early neurological deterioration: A randomized clinical trial" JAMA Neurol 2024; DOI: 10.1001/jamaneurol.2023.5093.

Secondary Source

JAMA Neurology

Source Reference: opens in a new tab or windowCucchiara B, Majersik JJ "The case of anticoagulation for progressing stroke: Have we come full circle?" JAMA Neurol 2024; DOI: 10.1001/jamaneurol.2023.5086.

Systemic infusion and local irrigation with argatroban effective in preventing clot formation during carotid endarterectomy in a patient with heparin-induced thrombocytopenia.

What I don't understand is why with that blockage the solution isn't just to completely close it up as long as the Circle of Willis is complete rather than go through the risks of endarterectomy? But I have no medical training so someone with that could explain why I'm wrong.
http://dgcases.docguide.com/systemic-infusion-and-local-irrigation-argatroban-effective-preventing-clot-formation-during-carotid?overlay=2&

A therapeutic dilemma exists when patients with symptomatic carotid stenosis and concomitant heparin-induced thrombocytopenia (HIT) are advised to urgently undergo carotid endarterectomy (CEA) with heparin therapy. After a 63-year-old man with HIT and multiple medical comorbidities underwent emergent coronary artery bypass grafting, postoperative imaging revealed plaque at the origin of the left internal carotid artery with 80%-99% stenosis and minimal contralateral internal carotid artery disease. During the patient's evaluation to undergo CEA for symptomatic high-grade carotid stenosis, enzyme-linked immunosorbent assay revealed persistent platelet factor 4 antibodies. The endarterectomy was successfully performed while the patient received argatroban, both as a continuous infusion and intermittent irrigation during dissection of the plaque. Postoperatively, the drip was continued for 24 hours, and the patient was discharged day 2 on a daily dose of 325 mg of aspirin. At the 6-month examination, Doppler ultrasound revealed normal anterograde velocities with no evidence of stenosis, and the patient noted no subsequent ischemic events. We now recommend systemic intravenous and local argatroban irrigation to prevent thromboembolic complications in CEA cases with HIT and renal insufficiency. Bivalirudin for both systemic intravenous use and local irrigation may be safer in patients without renal insufficiency because of its shorter half-life.

from: Department of Neurosurgery, University of Cincinnati College of Medicine and Comprehensive Stroke Center at University of Cincinnati Neuroscience Institute, Cincinnati, Ohio, USA.

as reported in: Serrone JC, Andaluz N, Brink V, Zuccarello M, Ware SL. World Neurosurg. 2013 Jul-Aug:80(1-2):222.e15-8. doi: 10.1016/j.wneu.2013.01.037.

See Published Case Report

Outcomes of Argatroban Treatment in Patients With Atherothrombotic Stroke - Japan

The failure could easily been because they were using invalid endpoints like the Rankin scale.
 The Rankin Scale has no useful discrimination at all. You should be using scans that show dead and damaged areas. 

Outcomes of Argatroban Treatment in Patients With Atherothrombotic Stroke - Japan

Observational Nationwide Study in Japan

1. Tomoki Wada, MD;
2. Hideo Yasunaga, MD, PhD;
3. Hiromasa Horiguchi, PhD;
4. Takehiro Matsubara, MD, PhD;
5. Kiyohide Fushimi, MD, PhD;
6. Susumu Nakajima, MD, PhD;
7. Naoki Yahagi, MD, PhD

+ Author Affiliations

1. From the Departments of Emergency and Critical Care Medicine (T.W., T.M., S.N., N.Y.) and Clinical Epidemiology and Health Economics, School of Public Health (H.Y.), The University of Tokyo, Tokyo, Japan; Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan (H.H.); and Department of Health Policy and Informatics, Tokyo Medical and Dental University, Tokyo, Japan (K.F.).

1. Correspondence to Tomoki Wada, MD, Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail wadat-eme@h.u-tokyo.ac.jp

Abstract

Background and Purpose—Argatroban, a selective thrombin inhibitor, is recommended for the use in patients with atherothrombotic stroke by the Japanese Guidelines for the Management of Patients with Acute Ischemic Stroke. We performed a nationwide Japanese study to investigate whether argatroban improved early stroke outcomes in patients with acute atherothrombotic stroke.

Methods—This retrospective observational study, using the Diagnosis Procedure Combination database in Japan, included patients who were hospitalized from July 1, 2010, to March 31, 2012, with a diagnosis of atherothrombotic stroke within 1 day of stroke onset. Patients were divided into 2 groups: those receiving argatroban on admission (argatroban group), and those who did not receive argatroban during hospitalization (control group). To balance the baseline characteristics and concomitant treatments during hospitalization between the 2 groups, one-to-one propensity-score matching analyses were performed. The main outcomes were the modified Rankin Scale score at discharge and the occurrence of hemorrhagic complications during hospitalization. An ordinal logistic regression analysis evaluated the association between argatroban use and modified Rankin Scale at discharge.

Results—After propensity-score matching, 2289 pairs of patients were analyzed. There were no significant differences in modified Rankin Scale at discharge between the argatroban and the control groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.88–1.16). The occurrence of hemorrhagic complications did not differ significantly between the argatroban and the control groups (3.5% versus 3.8%; P=0.58).

Conclusions—The present study suggested that argatroban was safe, but had no added benefit in early outcomes after acute atherothrombotic stroke.

Further argatroban study ‘warranted’ in acute stroke

Finally someone realizing how poorly tPA does. And studies from 2004 recommended more testing. God, how slow are we?
The 1995 research here: Only 17 years later, still nothing new
Thrombin inhibition in the acute phase of ischaemic stroke using argatroban
The 2004 research here:
Argatroban Anticoagulation in Patients With Acute Ischemic Stroke (ARGIS-1)
The 2012 one here:
Further argatroban study ‘warranted’ in acute stroke

Pilot trial findings suggest that combined treatment with intravenous tissue plasminogen activator (tPA) and the anticoagulant argatroban is worth pursuing.

In an editorial accompanying the study in Stroke, Philip Bath (University of Nottingham, UK) criticizes the trial for its lack of a placebo group, but also takes aim at issues and attitudes within the stroke community that made the small trial very difficult to complete.

The researchers report that 6.2% of the 65 patients in their study had symptomatic intracerebral hemorrhage or type 2 parenchymal hemorrhage. They hypothesized that a hemorrhage rate of up to 10% could be clinically acceptable if the addition of argatroban to tPA resulted in significant increases in recanalization rates.

Although tPA can be lifesaving, it results in a relatively low rate of recanalization,(look into pericytes) so co-treatment with an anticoagulant could theoretically improve recanalization and help to prevent reocclusion, leading to improved outcomes.

The patients were given standard tPA therapy, plus a 100 µg/kg bolus of argatroban followed by an infusion lasting 48 hours, which was adjusted to a target partial thromboplastin time of 1.75 times the baseline value.

Andrew Barreto (University of Texas, Houston, USA) and colleagues comment that three of the four significant hemorrhages occurred more than 18 hours into the infusion, and suggest that a shorter infusion could produce a better safety profile. However, they say that the hemorrhage rate in their study was similar to that observed in historical controls.

During the 2-hour infusion period, 55% of patients achieved sustained recanalization: 30% complete and 25% partial recanalization. At 24 hours, 78% of patients had recanalization, with 63% achieving complete recanalization.

Based on these recanalization rates, Barreto et al say that the combined treatment "may be better than tPA alone and as useful as any other intervention currently available, particularly considering the potential widespread applicability of this combined pharmacological approach." They therefore conclude that further research is "warranted."

In his editorial, Bath comments that research into anticoagulants in acute stroke patients remains active, despite numerous "neutral" trials, because of the possibility that they may augment recanalization.

Yet, he says, Barreto et al required more than 7 years to complete a study with just 65 patients, partly because "the investigators had struggled with a stroke community that was negative to the aims of the study on the grounds that combined thrombolysis and anticoagulation would inevitably be unsafe."

Bath says: "We as a stroke community must not allow our preconceived beliefs to obstruct trialists just because we think we already know the results. There are too many examples in which trial results have overturned dogma built on little or no evidence."

However, he also criticizes the study design, saying that "uncontrolled Phase II studies should be resisted by investigators, funders, sponsors, and regulators."