The treatment era of acute ischemic stroke began in December 1995 with the proof of benefit when intravenous thrombolysis was administered within 3 hours of onset (NINDS) in selected subjects.¹ Despite the scientific advance peripheral thrombolysis provided, translation of this benefit to stroke populations in the United States was slow. The next step in treatment was the demonstration of benefit in catheter-directed thrombolysis in the middle cerebral artery within 6 hours.² However, intra-arterial thrombolysis required cath lab availability, which was limited in the late 1990s. Even extension of the peripheral thrombolysis benefit from 3 to 4.5 hours due to the results of ECASS3 did not increase the number of treated patients.³ The next step in treatment had to await the development of stent retrievers for clot extraction. In December 2014, mechanical thrombectomy was shown to provide benefit beyond peripheral thrombolysis (MR CLEAN). And, by February 2015 multiple trials showed benefit with mechanical thrombectomy in the anterior circulation compared with peripheral thrombolysis (REVASCAT, Swift Prime, Extend IA, Escape). With the advent of advanced imaging identification of reversibly ischemic brain, the time window for treatments was extended up to 24 hours in selected cases (Defuse 3, DAWN). At last the tissue clock eclipsed the time clock for identification of those who might benefit from rescue treatment.

With these advancements more emphasis has been placed on systems of care beginning with public recognition of transient ischemic attack (TIA)/stroke, prehospital packaging, and development of comprehensive stroke centers with endovascular treatment expertise. Now more than ever where you go for health care can make a certain difference given rescue’s proven scientific benefit.

With the publication of NASCET in 1991, it was clear that activated carotid plaque with at least 70% stenosis was best managed by surgical removal (carotid endarterectomy). Subjects with 50% to 69% stenosis were the subject of another publication by the NASCET group in 1998. This group with moderate to severe stenosis had subgroups who were benefited with surgical revascularization. But included in the publication was a figure of the original NASCET cohort since 1991.⁹ The group with severe stenosis had ipsilateral strokes for 3 years, and then for the next 5 years had a stroke rate equal to those who had their carotid plaques removed. Only 25% of the group randomized to medical care had a subsequent stroke, but 75% did not. This graph suggested that despite severe symptomatic stenosis in a large
capacitance precerebral artery active plaques might become stable over time. But, the article did not indicate why or how this might have occurred.

Another example of the change in risk over time can be shown with the placebo groups in peripheral thrombolysis studies of acute ischemic stroke. The initial NINDS publication in 1995 had a placebo death rate of >20%.¹⁰ By 2008 (13 years later) in the extended time window study,¹¹ the placebo death rate was 8.2%. When death is less, the relative benefit from treatment is also less against the comparator. Trialists have experienced changing risk when vascular event rates were lower than predicted requiring expansion of their study population to retain statistical power.

The change (decrease) over time in levels of risk has been influenced by the advent of better antihypertensives, intensive lipid-lowering medications, and better access to cath labs for urgent reperfusion. And it may also be that the sickest have fallen first and earlier from the present (Darwinian selection). Historic risk may not be a guide to present or future risks as contemporary treatment(s) may have made a difference.