Stroke Clinical Trials

Clinical trial fails to show ticagrelor (Brilinta) superiority to aspirin in stroke prevention

The SOCRATES clinical trial has concluded with summary results having been released to the public. More detailed results will be presented at the European Stroke Organisation Conference in Barcelona, Spain next week.

Ticagrelor (Brilinta) carries a retail price in the United States of over $300/month. It was not found to be statistically more effective in preventing stroke in the SOCRATES study when compared with aspirin.

Ticagrelor (Brilinta) carries a retail price in the United States of over $300/month. It was not found to be statistically more effective in preventing stroke in the SOCRATES study when compared with aspirin. Source: GoodRx.com for price comparisons at retail pharmacies.

The trial randomized patients with transient ischemic attacks (TIA) considered to be high risk for stroke and patients with “mild” strokes to take either ticagrelor (Brilinta), a medication that impairs platelet function currently in use the prevention of heart attacks in patients with coronary artery disease or with coronary stents in place, or aspirin. Ticagrelor was taken at a dose of 90mg twice daily, and aspirin was taken at a dose of 100mg daily (plus placebo for the second dose – patients were blinded to which drug they were taking). Patients had to enter the trial within 24 hours of their TIA or stroke symptoms beginning. The endpoints were the amount of time until a recurrent stroke, a heart attack, or death. While the patients in the ticagrelor group are being reported as having fared slightly better than those in the aspirin group, the results were not statistically significant. This means that there is no significant benefit in the primary prevention of stroke after a TIA or in the secondary prevention of stroke following a mild stroke that ticagrelor carries over aspirin.

Aspirin for sale online in an assortment of packages from various producers. Image Source: GoodRx.com

Aspirin for sale online in an assortment of packages from various producers. Image Source: GoodRx.com

What does this mean? If you refer to the image to the left, you will see a big part of what it means

– about $300-plus per month in savings for some patients if they now opt for aspirin over a patented drug for which there is no generic equivalent.

It also raises the question about whether pharmaceutical companies will fund clinical trials that cost millions of dollars to run and carry to completion in order to obtain an additional indication for a drug’s use. It’s a gamble. If companies don’t fund trials to demonstrate efficacy, then insurers are less likely to cover drugs for patients, and patients are more likely to opt for a less expensive option, if available. If they fund trials and the drug being tested is not effective, or is not superior to a less expensive option that already widely exists, then not only is it millions down the drain, but negative press about the company and the drug. However, if the drug is shown to be more effective than the cheaper, more widely available option, then the return on investment could be huge.

Personally, I was shocked. Ticagrelor carries a reputation of being a potent antiplatelet medication, and many of us who treat patients with stroke or heart disease felt that this was a softball sort of trial. Of course the ticagrelor was going to win solidly – because it was being compared only to a substance that has been available over-the-counter for decades, a drug that went generic in the 1930s and whose history dates back over 2,000 years as a substance produced by the willow tree. Could it really be that something as simple and low cost as aspirin could rival an expensive, patented, relatively new prescription drug? According to SOCRATES, this may well be the case.

There were limitations to SOCRATES. It’s always difficult to incorporate every possible scenario into a clinical trial, especially in a disease like stroke where each one is different. This did not test whether the combination of aspirin and ticagrelor was more effective than aspirin alone. It also did not compare ticagrelor to other antiplatelet drugs that are generic, such as clopidogrel (Plavix). Medicine is still an art, because above all, it’s important to treat each individual patient with the information available while applying good judgment.

 

Transcranial direct-current stimulation (tDCS) at start of occupational therapy sessions yields more functional improvement after stroke, study demonstrates

A recent study published in the journal Science Translational Medicine earlier this month has demonstrated that an extra boost of electricity to the brain may result in improved upper limb use when combined with occupational therapy sessions following either ischemic or hemorrhagic stroke.

Transcranial direct-current stimulation (tDCS) has demonstrated in a small study to optimize the benefits of rehabilitative therapy for upper limb deficits after stroke. Graphic source: http://nwg.glia.mdc-berlin.de

Transcranial direct-current stimulation (tDCS); graphic source: http://nwg.glia.mdc-berlin.de

Twenty-four patients with upper limb impairment due to a stroke that had occurred at least six months previously were randomized to one of two groups. Patients in the treatment group received a small amount of direct electrical current, delivered via an electrode that was placed on the scalp over the motor cortex on the same side as the stroke. The second group of patients still had the electrodes in place, but no electrical current was being delivered. For the first 20 minutes of nine therapy sessions (one session per day, for nine consecutive days) the patients wore these electrodes. Following the 20 minute period, therapy continued as usual.

The idea was to determine if a small electrical stimulus could wake the brain up, so to speak. Neuronal plasticity is the term given to the concept that following a brain injury, surrounding cells can adapt to perform functions previously carried out by the cells that were damaged in order to restore function that may have otherwise been lost. While relatively small (24 patients participated in the study), there was a statistically significant improvement in upper limb movement in the patients receiving direct electrical current when compared to patients who did not receive electrical stimulation.

I always become intrigued (and excited) when options for stroke prevention or recovery that don’t involve more medications, surgical procedures, and/or significant risk to patients produce positive results, and this is such an example. This has the potential to be a sizeable step forward in producing better results with stroke rehabilitation, and larger studies are warranted. Perhaps what is most exciting is that the benefit was still seen three months later, despite patients not having not received electrical current stimulation during that time. This implies that the rehabilitation is effective and long lasting.

For more information about this study, click here.

 

Want to participate in a clinical trial? Try clinicaltrials.gov!

There is still a vast amount that remains unknown in the world of stroke treatment, particularly when it comes to managing what comes after the initial hospitalization and rehabilitation process. Fatigue, pain, insomnia, anxiety, depression, spasticity, walking deficits, headaches, dizziness, visual symptoms – sometimes our typical approaches to managing these symptoms do not seem to be as effective after a brain injury. For example, patients with thalamic pain syndrome after an injury to a part of the brain known as the thalamus often struggle with uncomfortable pain, tingling, burning, and/or a sensation of “tightness” around an arm or a leg, and they may quickly exhaust all of the available options. Medications that are generally effective for many painful conditions frequently fail to provide relief for this patient population. Once healthcare providers and patients are both out of ideas, the question about available clinical trials arises.

Clinicaltrials.gov contains information on more than 206,000 clinical studies.

Clinicaltrials.gov contains information on more than 206,000 clinical studies.

Clinicaltrials.gov is a fantastic resource available for physicians, investigators, and patients, but the problem is – many patients are unaware of its existence. It is a registry of most clinical trials involving human subjects in the U.S., and also includes information about thousands of trials taking place in other nations. Currently, the site contains information about more than 206,000 studies!  If one is seeking study information on Fabry disease, a relatively rare genetic disorder that can result in stroke at a young age, as of this post’s publication date 102 results were identified from searching on the term “Fabry.” Nations outside of the U.S. have also created their own registries. In Europe, for instance, the EU Clinical Trials Register serves the same purpose. Similar registries are available in South Korea, Japan, and Australia, to name a few others.

If you feel you are out of therapeutic options, regardless of what medical situation you may face, I encourage you to try an easy search through an online clinical trials registry. This information is free of charge, and can empower patients as they navigate through complex conditions and symptoms. Type the name of your diagnosis in the search bar, regardless of how rare it is, and allow yourself to explore. Not only might it be beneficial for you as a patient to consider a clinical trial if there are no known answers, but the more willingness there is on the part of patients, physicians, and investigators to participate in research, the sooner the answers that have evaded us will come.

Clinical trial shows no difference in stroke prevention between antiplatelet agents and anticoagulation in carotid or vertebral artery dissection

Due to the number of readers of The Stroke Blog who have identified themselves as having experienced carotid or vertebral artery dissections with or without stroke, I believe a clinical trial from the United Kingdom is very much worth sharing here.

The Cervical Artery Dissection in Stroke Study (CADISS – Markus HS, et al) set out to answer a question that has existed for many decades in the world of stroke management. When a dissection (a tear in the innermost tissue layer of an artery) of a carotid artery or vertebral artery (arteries in the neck that bring blood to the brain), how is a stroke best prevented going forward? In patients who have already had a stroke at the time the dissection is diagnosed, the goal is certainly to prevent further strokes from occurring. If a patient has not already sustained a stroke, then sparing that person a permanent brain injury is the top priority. It has not been entirely clear how to achieve these goals though. Should a patient be treated with antiplatelet agents (medications impairing platelet function), such as aspirin, clopidogrel (Plavix), another antiplatelet agent, or some combination of these? Or should a patient be treated with anticoagulation, a drug that actively prevents clotting, such as warfarin (Coumadin) or heparin?

I have heard many arguments on all sides. Some neurologists say that antiplatelet therapy is just as effective as warfarin but carries a lower risk of hemorrhage. Others say that antiplatelet therapy is not aggressive enough and anticoagulation with warfarin or heparin (or both) should be used. Some say to start on antiplatelet therapy or anticoagulation and if symptoms get worse to switch to whatever therapy was not initially used. Others argue for placing a stent in the dissected artery. Until recently, there was no clinical trial actually comparing antiplatelet therapy to anticoagulation in patients with carotid artery or vertebral artery dissection, and the medicine selected for treatment was based entirely on anecdotes and the bias of the treating physician.

In the CADISS trial, patients presenting to one of the participating medical centers in the United Kingdom who were diagnosed with carotid or vertebral artery dissection (with or without stroke) believed to have occurred within the seven days prior to presentation were randomized. Half of the patients were started on antiplatelet therapy, and half were placed on anticoagulation. The duration of treatment was three months. The endpoint was to determine how many strokes or deaths occurred in each group. Whether or not the patient had already had a stroke before enrolling in the trial, the endpoint was to see, once antiplatelet therapy or anticoagulation was started, how many patients went on to have strokes despite that therapy.

The CADISS trial, published in Lancet Neurology in April 2015, did not find a statistically significant difference in stroke prevention in patients presenting with acute carotid or vertebral artery dissections when treated with either antiplatelet therapy or anticoagulation.

The CADISS trial, published in Lancet Neurology in April 2015, did not find a statistically significant difference in stroke prevention in patients presenting with acute carotid or vertebral artery dissections when treated with either antiplatelet therapy or anticoagulation.

Two hundred fifty patients were enrolled (118 carotid artery dissections and 132 vertebral artery dissections). Interestingly, 52 of these patients were not found to have carotid or vertebral artery dissections when their radiology studies were carefully reviewed as part of the study, despite initially receiving that diagnosis. Of the 198 patients remaining, there was no significant difference in strokes between the two groups. There was one episode of symptomatic bleeding in the anticoagulation group (subarachnoid hemorrhage, or bleeding in the brain that occurs when an artery in the brain ruptures). There were no deaths in either group. Of the 198 patients with radiological evidence of dissection confirmed, there were only four total strokes following initiation of the designated medical therapy in both groups combined.

The CADISS trial began as a feasibility study – a trial to see if it was even feasible to enroll enough patients with a condition not diagnosed with frequency in the emergency department. This phase of the study was statistically sound and convincing enough not to proceed with a larger trial.

A trial comparing stenting to medication alone has not been performed, and given the low number of strokes in patients on medical therapy in the CADISS trial, it is unlikely that a dissection stenting trial will be performed any time in the near future.

For more details about arteries bringing blood to the brain and about carotid and vertebral artery dissection, please refer to a prior post on The Stroke Blog by clicking here.

The take-away points from CADISS are as follows:

  1. The overwhelming majority of patients with carotid and vertebral artery dissection, if started on either antiplatelet therapy or anticoagulation soon after the dissection has occurred, will not go on to have a stroke while on therapy during the aftermath following the vascular injury.
  2. There is no significant difference in stroke prevention in patients with carotid and vertebral artery dissection between those using antiplatelet medications and those using anticoagulation.

The trial does not address the myriad symptoms many dissection patients notice lingering after the injury – migraines, neck pain, and anxiety, to name a few. One trial cannot address every possible issue associated with a medical condition. However, physicians who care for young stroke patients with this particular vascular injury should be celebrating the fact that we finally have evidence-based guidance for preventing stroke in these patients.

Mechanical thrombectomy makes a comeback in treating acute ischemic stroke

Intravenous (IV) t-PA, a “clot-busting” drug approved by the FDA for the treatment of acute ischemic stroke within three hours of the start of symptoms, has been recognized as the standard of care since the pivotal NINDS clinical trial that demonstrated reduced level of disability 90 days after ischemic stroke in eligible patients who received it. However, the subject of acute treatment with the use of thrombectomy has remained controversial until recently. Thanks to recent clinical trial results, the American Heart Association/American Stroke Association guidelines have now been updated recommending the use of this procedure in eligible patients meeting appropriate criteria.

Depending on the geographical region and practices, approximately one to 25% of acute ischemic stroke patients will receive IV t-PA, with the national average being around six to ten percent. Questions that have continued to plague physicians delivering care to this patient population include:

  • What, if anything, can be offered to patients who are not eligible for IV t-PA, but who still present to the hospital within hours of stroke onset?
  • What should be done for patients who have received IV t-PA, but who are failing to improve clinically, and there is a known blood clot that remains in a major artery of the brain?

A mechanical thrombectomy is a procedure performed with a catheter (a specialized type of wire) with the intention of physically removing the clot if it is not dissolving on its own or with the assistance of IV t-PA. A mechanical thrombectomy can be performed either with or without the administration of a dose of t-PA directly from the catheter within the artery at the site of the clot.

MERCI clot retriever (ref: Medscape)

MERCI clot retriever (ref: Medscape)

An early catheter for this procedure was the Merci Clot Retriever. Its tip is shaped like a corkscrew, with the goal being to spear a clot and extract it from the artery, restoring blood flow. This was followed by a suction device, made by Penumbra, which aimed essentially to vacuum the clot from the artery. Despite the excitement around

Penumbra vacuum suction catheter - from Penumbra site

Penumbra vacuum suction catheter – from Penumbra site

offering patients these procedures in the acute stroke setting, the outcomes trials were discouraging, largely failing to show improved functional outcomes for patients  than they could achieve with IV t-PA.

Graphic of a stent retrieval device for clot removal

Graphic of a stent retrieval device for clot removal

This has changed in the past year though. Five papers have been published within this timeframe showing improved functional outcomes with mechanical thrombectomy with early therapy intervention. The newer retrieval devices involve the use of wire stents to extract the clot, and the result has been less time required to open the artery to restore flow to the brain. A key difference between these more recent trials and the failure to demonstrate improved outcomes in previous mechanical thrombectomy trials is likely due to the more rapid restoration of flow. The mantra of “time is brain” still holds true. The recent trials have shown what is possible when a team of healthcare professionals collaborate effectively to start the procedure as soon as possible. While thrombectomy may have been available for years, waiting on a key person to become present when the others are ready to start creates delays.

The updated guidelines from the American Heart Association/American Stroke Association emphasize the importance of continuing to treat patients with IV t-PA who are candidates for the drug. After all, IV t-PA can be administered quickly, its benefit has been proven, and it should not be withheld in eligible candidates. However, mechanical thrombectomy with stent retrieval devices provides another tool in the battle against acute ischemic stroke.