The RAMER Reviews: The ARAMIS Trial
By: Mitchell Melikhov-Sosin MD
Edited by: Timothy Khowong, MD, MSEd
Strokes are a significant cause of morbidity and mortality in the USA and a leading contribution to long term disability. Understanding this, we as a medical community take strokes seriously. EMS, triage nurses, and physicians all know their role in early identification and action. We do everything we can to get the patient to early revascularization usually with tPA, a “clot buster”, or sometimes even endovascular retrieval. As the old adage goes: “Time is brain”.
However, we also know that tPA is not risk free and can be associated with significant side effects. The original FDA approval data from the late 1990s showed a hemorrhagic conversion rate of 6% in the first 48 hours after receiving tPA. Though follow up studies suggest complication rates around 50% of initial estimates, this is still a serious problem. Patients who are candidates for tPA (and their families) are tasked with making a serious health decision with high complication rate while under immense time pressure. Of course, this is not a high-pressure sales tactic for a used car and the main issue is time = tissue, but the comparison still drives home the point about urgency and lack of time to think from the standpoint of patients and families.
Researchers from China came up with an interesting question: Can we find the subset of strokes that would normally get tPA, and get the same benefit without the consequences by using DAPT instead of tPA?
The ARAMIS clinical trial was a large study performed at 38 hospitals in China. It was an open-label non-inferiority trial comparing traditional tPA versus DAPT for acute, non-disabling stroke of <4.5hrs. This is key. They looked at patients with presenting with NIHSS of 5 or less. However, if they had any contributions to the score they felt were “not mild” they would just go with traditional tPA. For example, patients with vision, neglect, single limb, speech symptoms with NIHSS = 1 would still be considered a non-mild / disabling stroke and be excluded from the study to be given traditional tPA.
They looked at a few outcome measures. The primary outcome was excellent functional outcome at 90 days, defined at modified Rankin Scale (mRS) 0-1. The secondary measure was favorable functional outcomes at 90 days, mRS 0-2. And their main safety outcome was symptomatic intracranial hemorrhage up to 90 days. So, this leads us to the next important exclusion groups: those with mRS = 2 or more and those with prior ICH. They probably felt that those with prior ICH were too high of a risk of repeat bleed.
This study needed >600 patients to be powered to >80% and they achieved that with 760 patients of whom 719 were analyzed. But there was a big catch: there was a 20.4% crossover rate. It’s mostly attributed to “protocol violation” and certainly raises questions about the validity and generalizability of the results. Though, it’s important to point out that there was a lot of statistical analysis performed and they showed a significant similarity between groups being preserved even after the crossover.
Results for Primary and Safety outcomes were as follows:
There was no difference in secondary outcomes other than fewer patients in the DAPT group having early neurological deterioration compared to the tPA group (4.6% vs 9.1%; -4.5%; 95% CI -8.2 to -0.8%). Basically, since we know that the bad outcomes from strokes and the medications to treat them are more likely to rear their ugly heads in the first hours and days, the investigators looked at the first 24 hours to measure for early worsening. They found the DAPT group did better, which makes sense given the risk profile compared to tPA.
While the study suggests that DAPT therapy is non-inferior, cheaper, and has fewer side effects than tPA in patients with mild, non-disabling strokes there were a few issues. First of all, it was conducted in China and had mainly East Asian participants. There were also significantly fewer women in the study than men. This study may not be generalizable to other areas with a different demographic composition. The same morbidity, mortality, and disability statistics regarding strokes run true in China has in the USA, but even more so. Strokes are an even higher contribution to those population health measures than they are in the USA. For us here at New York Presbyterian Queens in 2023, this might be more generalizable considering we have many patients of East Asian ancestry. Ultimately though, the crossover aspect leaves many questions unanswered and is difficult to overlook. It makes applying the results of this study difficult until further studies can replicate the results in more places, with more diversity, and more adherence to protocol.
Of course, that would be hard too since it’s difficult to conduct a trial that does not offer the standard of care to patients especially with such a high impact illness like stroke. IRBs in the USA and similar countries would need a lot of convincing to ethically allow for this, although it did happen such as with the PRISMS trial. Until then, we will look to other places for trial in this area.
References
Chen H, Cui Y, Zhou Z, et al. Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial. JAMA. 2023;329(24):2135–2144. doi:10.1001/jama.2023.7827
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401. PMID: 7477192.
https://rebelem.com/the-aramis-trial-dapt-vs-alteplase-in-minor-nondisabling-acute-ischemic-stroke/
Khatri P, Kleindorfer DO, Devlin T, et al. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018;320(2):156–166. doi:10.1001/jama.2018.8496