Secondary prevention of acute ischemic stroke

Warfarin-Aspirin Recurrent Stroke Study (WARSS, 2001)
This trial randomized 2,206 patients with prior ischemic stroke (within 30 days) to receive aspirin 325 mg daily + placebo vs. warfarin 2 mg daily (dose adjusted) + placebo to maintain INR 1.4-2.8. False INR values were used in the group receiving aspirin and placebo to maintain blinding. More than half of the patients had lacunar infarcts as the prior stroke. Recurrent ischemic stroke or death occurred in 17.8% of the warfarin group and 16.0% of the aspirin group (p=0.25). There was a trend for more major hemorrhage in the warfarin group (2.2% vs 1.5%, p=0.10), and a significant increase in minor hemorrhage in the warfarin group (20.8% vs 12.9%, p < 0.001). Therefore these was no benefit of warfarin over aspirin in these patients, with a slight increased risk of hemorrhage.

Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS, 2017)
This trial randomly assigned 27,395 non-stroke patients with vascular disease (coronary artery disease, peripheral vascular disease) to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, and compared with rivaroxaban 5 mg twice daily or aspirin 100 mg once daily, with a primary outcome of a composite of cardiovascular death, stroke, or MI. The trial was stopped early, as the primary outcome occurred in 4.1% of the rivaroxaban + aspirin group, compared with 5.4% in aspirin alone (HR 0.76, 95% CI 0.66-0.86). This result was mainly driven by a decrease in ischemic stroke (0.7% vs 1.0%, OR 0.51, 95% CI 0.38-0.68). There was not an increase in the risk of hemorrhagic stroke for the combination (rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily), but there was for the higher dose rivaroxaban alone (5 mg twice daily) vs. aspirin alone. In a secondary analysis, most of the ischemic strokes prevented with the combination seemed to be cardioembolic or stroke of undetermined cause.

Blood pressure control
After ischemic stroke, it is reasonable to control SBP to <130/90 for the prevention of recurrent stroke (predominantly prevention of intracerebral hemorrhage).
 * Trials
 * 2013 SPS3 trial: 3,020 patients with recent lacunar infarction randomized to goal <130 mmHg. or SBP 130-149 mmHg or There was a trend toward reduction in all strokes (HR 0.81, 95% CI 0.64-1.03) in the <130 mmHg group, which was driven by predominantly a decrease in intraparenchymal hemorrhage (OR 0.37, 95% CI 0.15-0.95).
 * 2016 PAST-BP trial: 529 patients with a history of stroke or TIA randomized to goal SBP <130 mmHg or <140 mmHg. There was a trend toward reduction in stroke with the intensive group (HR 0.14, 95% CI 0.01-2.72)
 * 2017 PODCAST trial: 83 patients with a recent ischemic or hemorrhagic stroke, randomized to <125 mmHg or <140 mmHg. Very small numbers, but there were slightly fewer strokes in intensive group (HR 0.34, 95% CI 0.04-3.15)
 * 2019 RESPECT trial: 1,280 patients with a history of stroke (in prior 3 years) randomized to <120/80 or <140/90. There was a trend toward reduction in recurrent stroke of any type (HR 0.73, 95% CI 0.49-1.11) in the intensive group, which was driven predominantly by a decrease in intraparenchymal hemorrhage (HR 0.09, 95% CI 0.01-0.70).
 * Meta-analyses
 * 2018 Cochrane Review of 11 studies: 38,742 patients. There was a pooled risk ratio of intensive blood-pressure lowering of 0.80 (95% CI 0.63-1.00) for recurrent stroke, and 0.58 (95% CI 0.23-1.46) for major vascular event.  No specific BP target goal could be suggested since studiesused different targets.
 * 2019 Meta-analysis as part of RESPECT trial: including SPS3, PAST-BP, PODCAST trial, and now RESPECT trial. There was a significant reduction in stroke of any type (HR 0.78, 0.64-0.96).

LDL and statins
Statin therapy is of benefit after ischemic stroke and should ideally target an LDL goal of <70 mg/dL. If this target is not achieved within 6 months then adding ezetimibe is reasonable, and LDL should be followed every 6 months thereafter. In 2006 the SPARCL trial showed that, in patients who had a stroke/TIA and who had LDL levels of 100-190 mg/dL, 80 mg of atorvastatin started within 1-6 months reduced the risk of subsequent stroke (aHR 0.84, 95% CI 0.71-0.99) or cardiovascular events (aHR 0.80, 95% CI 0.69-0.92). Subsequent analysis of SPARCL suggested that patients who achieved lower LDLs of <70 mg/dL were likely to have greater benefit, but no trial data existed to prove that a lower LDL was better. In January 2020, the Treat Stroke to Target Trial was published, including 2860 patients with stroke in the prior 3 months or TIA in the prior 15 days, to target LDL of <70 mg/dL or 90-110 mg/dL using statins initially followed by ezetimibe if needed. The trial showed fewer major cardiovascular events in the lower target group (8.5%) vs higher-target group (10.9%) for NNT 42, HR 0.78 (95% CI 0.61-0.91), without any significant safety issues. There was only a trend toward improvement for ischemic stroke or TIA (8.4% vs 9.7%, HR 0.87, 95% CI 0.68-1.11) but the study was underpowered for this outcome.

A 2022 meta-analysis of 11 randomized trials and 20,163 patients with stroke, the NNT for 4-year stroke prevention was 90 (absolute risk 8.1% vs 9.3%), NNT to prevent a major cardiovascular event was 35, and number needed to harm to cause a hemorrhagic stroke was 242. This result was found in trials of patients with atherosclerotic disease, not in those without. Benefit does not otherwise depend on the type of lipid lowering therapy provided.

Triglycerides
Data suggests that elevated triglycerides (defined as ≥150 mg/dL) are associated with an increased risk of major cardiovascular events.

Carotid stenosis
NEEDS FULL EDITING

Follow-up
Early follow-up with primary care is essential. In an analysis of the PharMetrics database, readmission within 30-days of infarction occurred in 7.3% of patients, and within 90 days in 13.7% of patients. Most readmissions were for acute ischemic stroke. Follow-up with primary care within 30 days was associated with a reduced rate of readmission (HR 0.84, 95% CI 0.72-0.98). Therefore, early follow-up with primary care is important. Follow-up with primary care within 30 days may reduce readmissions by 16%, for a NNT of 6.