When less is more (brain)—comment on “Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage”

We have known that “time is brain” for a few decades. Marler et al first published the now canonical graph showing the declining odds of good outcome with every minute delay after stroke onset. Emberson, Lees, and others confirmed and extended the now-famous graphic using pooled analysis of patient-level data from nearly every modern randomized, placebo-controlled trial of alteplase for acute ischemic stroke. Saver quantified the mantra using inferences from primary biology; with every minute of untreated ischemia our patients lose almost 2 million brain cells. Every innovation that comes along seeking to improve stroke treatment—a new imaging technique, a new biomarker, a new adjunct to thrombolysis or thrombectomy—must overcome the “time is brain” barrier if it will enter clinical use. For example, advanced vascular imaging of acute stroke patients—first proposed by Lou Caplan >20 years ago—failed to enter the mainstream standard practice until modern thrombectomy treatment proved the invested time paid off. The increasing use of novel oral anticoagulants (NOACs) presents a new conundrum for the Code Stroke team. Data clearly show that NOACs prevent embolic stroke in selected atrial fibrillation patients, with either no increase or actual reductions in cerebral hemorrhage rates. Because we avoid thrombolysis in patients taking vitamin K antagonist anticoagulants, by analogy we hesitate to offer thrombolytic therapy to patients reported to be taking NOACs. Several investigators have suggested that a rapid, reliable way to measure NOAC blood levels in acute ischemic stroke could guide clinical decision making. In this issue of Annals of Neurology, Seiffge et al report elegant results from the Novel Oral Anticoagulants in Stroke Patients (NOACISP) study. The authors measured rivaroxaban levels in stroke patients presenting acutely with either ischemic or hemorrhagic stroke and sought to determine whether such levels could guide decision making. The authors used a prespecified cutoff value above which clinicians should avoid tissue plasminogen activator in ischemic stroke (100ng/ml), and another level above which clinicians should consider reversal agents in acute hemorrhages (75ng/ml). Patients (n 5 241) were identified in a large network of European stroke centers, and the basic enrollment/data collection procedures were handled in standard fashion. The acute ischemic stroke patients (n 5 113) and the intracerebral hemorrhage patients (n 5 51) all stated they had taken a dose of rivaroxaban within 48 hours of their last known well time; the patient demographics matched the typical stroke study population; rivaroxaban levels were associated with dose taken, renal function, and time since last dose, all suggesting the sample reflects a realistic study population. The authors found that blood rivaroxaban levels did not differ between patients presenting with ischemic versus hemorrhagic stroke. Using the predefined cutoff values, about half the patients with ischemic stroke had “elevated” levels of rivaroxaban and about two-thirds of the hemorrhages showed rivaroxaban levels high enough to consider reversal agents. To interpret the NOACISP results, one first might consider the current context around using thrombolysis in acute stroke. The notion that thrombolysis causes harm in patients taking anticoagulants, although logical, has few data to support it. Retrospective reviews suggest that thrombolysis in the setting of warfarin use is safe if the international normalized ratio (INR) is< 1.7. In patients whose medication-induced INR was> 1.7, no evidence of increased hemorrhage risk could be found in thrombolysed patients. The NOACISP authors themselves have published retrospective data suggesting flat or possibly reduced cerebral hemorrhage rates in thrombolysed patients who were taking NOACs or vitamin K antagonists. Not only do limited data suggest that using thrombolysis in the presence of anticoagulants is safe, there is considerable evidence that thrombin inhibitors are vasculoand neuroprotective. The direct thrombin inhibitor argatroban was shown to be powerfully neuroprotective using a functional assay and to significantly reduce lesion