This Year in Stroke Prevention: A Review of New Trial Data

In this podcast, Neurology Learning Network's Stroke & Vascular Section Editor Amrou Sarraj, MD, gives a snapshot of key stroke prevention trial data that were unveiled in 2020—the THALES trial, the RIVER trial, and the Treat Stroke to Target Trial. A full transcript is provided below.

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Amrou Sarraj, MD, is an associate professor of neurology at McGovern Medical School at UTHealth in Houston, Texas.

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References:

  1. Amarenco P, Denison H, Evans SR, et al. Ticagrelor added to aspirin in acute ischemic stroke or transient ischemic attack in prevention of disabling stroke: A randomized clinical trial. JAMA Neurol. Published online November 7, 2020. doi:10.1001/jamaneurol.2020.4396
  2. Amarenco P, Kim JS, Labreuche J, et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020; 382:9-19. doi:10.1056/NEJMoa1910355
  3. Guimarães HP, Lopes RD, de Barros e Silva PGM, et al. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve. N Engl J Med. 2020; 383:2117-2126. doi:10.1056/NEJMoa2029603

Transcript:

Amrou Sarraj, MD: Greetings. This is Dr Amrou Sarraj. I'm an associate professor of neurology and vascular neurologist at UT McGovern in Houston. In this podcast, we will do a year‑in‑review summary of the main clinical trials and major papers that were published within the last year or so, focusing on the different main categories of our daily stroke neurology practice.

We will go over stroke prevention. We will discuss the new data on potential extension of the IV thrombolysis beyond four and a half hours. We will go over the different recent trials and major papers that were published around thrombectomy with its different subcategories. We'll conclude with the data of the management of hypertensive intracerebral hemorrhage.

This will be an overall review of the data. We'll go over the question of the trial or the paper, the main results, and the conclusion how this applies to the practice. There will be a summary document available with this podcast for people who would like to see the details of the numbers with references to all of the papers and trials that I will be going over.

We will start with stroke prevention. There were trials that were published within the last year or so that can apply to the daily practice. The first one is THALES. THALES looked at secondary prevention of mild strokes—stroke scale NIHSS of 5 or less—or TIAs focusing on whether ticagrelor and aspirin would be superior to aspirin alone in this population.

We have usually a lot of patients in our practice that we may sometimes run out of options on which antiplatelet agent to use when we believe that the etiology is cerebral atherosclerosis or small vessel disease.

For a long time, the options were limited to aspirin, clopidogrel, and Aggrenox. Now with ticagrelor, probably there will be a new option available. Ticagrelor has been used more frequently in the cardiology world. Brilinta is the generic name for that.

This trial randomized over 11,000 patients in almost 400 centers into 2 arms—ticagrelor and aspirin vs aspirin and placebo. The main outcome was composite outcomes of stroke and death at 30 days. This outcome occurred less frequently in the ticagrelor and aspirin arm. This was statistically significant.

Also, stroke occurrence was less in the ticagrelor and aspirin arm. However, this was associated with more severe bleedings. However, with the large number of patients, this was statistically significant. Intracerebral hemorrhage or fatal bleeding were also more common in the ticagrelor arm. The discontinuation of the medication by the patients due to bleeding occurred more in the ticagrelor arm.

The conclusion from this is, in this subpopulation of patients with mild strokes or TIAs, that ticagrelor and aspirin combination was superior in decreasing the risk of the composite outcomes of stroke or death at 30 days. However, this was associated with more severe bleedings in the ticagrelor arm.

I am one of the people who have been using this, especially with this data. I believe when we have such results, we will see how this applies to the practice. There will be definitely follow‑up studies that look at the side effects and efficacy in real-world practice. Hopefully, we have a new option to treat these patients.

The second trial, also within prevention, was the RIVER trial that was done in Brazil, 49 centers. This trial looked at rivaroxaban vs warfarin in patients with atrial fibrillation or flutter bioprosthetic mitral valve as an option for stroke, TIA, or systemic embolism, valve thrombosis, and hospitalization for heart failure prevention.

Since the direct anticoagulant, or what used to be known the NOAC, the novel oral anticoagulant, came out to practice in the last few years based on randomized trials, those were restricted to the population of patients who had atrial fibrillation without bioprosthetic valve, nonvalvular atrial fibrillation. We were not able—it was not indicated to use for those in patients with valvular atrial fibrillation.

This trial looked at this specific question and randomized patients to rivaroxaban 20 mg once daily vs warfarin with INR goal of 2.0 to 3.0. Those are usually noninferiority trials. They attempt to show that the new agent is non‑inferior in the prevention as compared to the agent in practice.

The RIVER trial did show that. It did show that rivaroxaban was non‑inferior to warfarin in respect to the mean time until the primary outcome of the best major cardiovascular event or major bleeding at 12 months occurred.

The occurrence of ischemic stroke was numerically lower with rivaroxaban. This did not meet statistical significance however. The death was also numerically lower. The stroke was lower with rivaroxaban and this was statistically significant.

This presents a new option in patients with valvular atrial fibrillation or flutter that can be helpful, especially with the difficulty with checking INR frequently with compliance with Coumadin with the fact that the therapeutic levels probably in a significant number of patients are not there all the time, about one‑third of the patients. Hopefully, this helps in giving a new option to this subpopulation.

The next study in ischemic stroke prevention was focused on lowering the LDL level. The trial, which was the Treat Stroke to Target Trial, was published during the last year in New England Journal of Medicine. It took place at 77 sites in France and South Korea, and extended over a long period between 2010 and 2018, enrolled around 3000 patients—2860 patients.

The population was adults, 18 or older, with recent ischemic stroke within the last 3 months and stable neurologic deficit or TIA within 15 days with atherosclerotic disease of the cerebral artery or the coronary artery or the aorta. The presumed stroke etiology was cerebral atherosclerosis.

The aim of the study was to evaluate a target level of LDL cholesterol less than 70 vs a target of 90 to 100, lower target LDL vs higher target LDL and see if lower target LDL would result in better stroke and TIA and cardiovascular events prevention.

It's well known that higher cholesterol level, especially LDL, is a risk factor. Data from the SPARCL study in the past showed that statin and a goal of less than 70 would result in reduction of stroke recurrence.

This trial wanted to look at different targets with aggressive lipid‑lowering vs less aggressive or moderate lipid‑lowering. The target goal of less than 100 is usually used in the cardiology literature.

The primary outcome of the trial was a composite outcome of nonfatal stroke, nonfatal MI, unstable angina with the urgent need for intervention, a TIA with the urgent need for carotid revascularization, or unexplained death.

This was a timed event analysis. The patients were followed for a median of 3 and a half years in both arms, the aggressive lipid‑lowering vs the moderate lipid‑lowering. There were patients that were followed up to almost 7 years. The results showed a lower frequency in the primary end point.

The composite outcome of stroke or cerebrovascular disease, or cardiovascular disease, or death occurred in the aggressive lipid‑lowering arm in 8.5% as compared to 10.9%. That was statistically significant on hazard ratio analysis. It was a pre‑specified adjusted analysis, which was also statistically significant and showed a similar effect.

It's important to notate that two‑thirds of the events that make the primary composite outcome were nonfatal strokes. This is very relevant to the stroke literature. The secondary endpoints were also looked at. Those included only nonfatal stroke, only nonfatal MI, among others. None of those were statistically significant.

The conclusion of this trial is, in patients with recent ischemic stroke or TIA with evidence of atherosclerotic disease, that lowering the LDL cholesterol to a level of less than 70 mg/dL exhibited lower risk of the composite outcome of major cardiovascular event as compared to patients with target LDL level of 90 to 100.

As we know, prior evidence from the SPARCL trial showed that atorvastatin, or Lipitor, with a target of less than 70 of the LDL showed reduction in stroke and cerebrovascular events recurrence.

This trial came in to look at different targets—aggressive target of less than 70, vs more moderate target of 90 to 100. Usually, less than 100 is the target in the cardiology literature and practice more than the stroke practice.

Why this is important? Many patients may stop using statins because of the potential side effects—muscle ache, among others. Having a more moderate target could be effective without causing the side effects. On the other side, it's important to know if we need to go for a lower target, which what this trial attempted.

The regimen that was used was left to the investigators, which is very important to the generalized ability. Any statin plus Zetia were the medications used in the trial. That's very important to the generalizeability, that there was no one medication that was used.

How this is applicable to a lot of practice? This trial showed that lower lipid target of LDL less than 70 is more effective in a randomized trial as compared to 90 to 100. Probably this is what should reflect in our practices.

The patients were followed, as I mentioned, up to almost 7 years as a range, but the median was 3.5 years. Their LDL were checked every 6 months. The patients in the aggressive treatment group with a LDL target less than 70 were within the desired range and around 53% of the cases as compared to 32% of the patients in the moderate lipid‑lowering arm.

Thank you for listening to this year‑in‑review podcast. This first part was on the major trials that were published in 2020 on stroke prevention. Please join us in the next podcast on thrombolysis and new data within the last year, and the third one on thrombectomy major trials and new data, all in the last year. Thank you.