The CREST-1 trial [
14] has been the main driver of recent recommendations in some guidelines that CAS is a suitable (even equivalent [
32]) alternative to CEA in patients with ACS and/or SCS. In CREST-1, among all 2502 mixed symptomatic and asymptomatic patients, CAS was not as effective as CEA because it caused nearly twice as many strokes as CEA within the 30-day post-procedural period with a hazard ratio (HR) of 1.8 and 95 % confidence interval (CI) of 1.1–2.8 (
P = 0.01). The first 30 days following a procedure is the period of highest risk for procedure-associated adverse events and where significant treatment differences most often appear. In CREST-1 the CAS-related stroke excess was still evident in 4 years at study end (HR 1.4, CI 1.0–2.1,
P = 0.049), particularly if periprocedural death was included (HR 1.5, CI 1.1–2.2,
P = 0.03) [
14]; however, in CREST-1 myocardial infarction (an adverse or safety outcome) was used in a balancing act to show no ‘statistically’ significant difference between CAS and CEA in the chosen primary outcome measure (30-day periprocedural stroke, death or myocardial infarction or any ipsilateral stroke within 4 years of randomization) [
14]. As well documented, in CREST-1, among all 2502 mixed symptomatic and asymptomatic patients, periprocedural clinically defined myocardial infarction was twice as common with CEA than CAS (28 versus 14 myocardial infarctions) [
9,
14]. However, periprocedural stroke was nearly twice (1.9 times) as common as periprocedural clinically defined myocardial infarction (81 strokes versus 42 myocardial infarctions) and approximately 1.3 times as common as myocardial infarction defined clinically or with biomarker change only (81 strokes versus 62 myocardial infarctions) [
9,
14]. Because periprocedural stroke was more common than periprocedural myocardial infarction in CREST-1, CAS still caused more of these clinically defined adverse outcomes than CEA (66 versus 57), although this did not reach statistical significance (HR 1.2, 95 % CI 0.8–1.7,
P = 0.38) [
14]. The incidence of myocardial infarction beyond the 30-day periprocedural period was not reported [
9,
14].
In randomized trials of CAS versus CEA, where both 30-day periprocedural outcomes were reported, stroke (most caused by CAS) was overall approximately 4.5 times as common as periprocedural clinically defined myocardial infarction [
12,
14‐
16,
22,
26]. A meta-analysis of all available randomized trials of CAS versus CEA (providing larger patient numbers than in CREST-1 alone) demonstrated among symptomatic patients a statistically significant higher risk of 30-day periprocedural stroke, death or myocardial infarction with CAS (odds ratio, OR 1.44, 95 % CI 1.15–1.80,
P = 0.002) [
11], while the rate of ipsilateral stroke after the periprocedural period did not differ between treatments (OR 0.93, 95 % CI 0.60–1.45,
P = 0.76) [
11].
No randomized trial has been sufficiently powered to test for a difference in rate of stroke with or without myocardial infarction in ACS patients alone; however, the direction of effect in CREST-1 (largest relevant randomized trial) was indicative of approximately double the rate with CAS (HR 1.86, 95 % CI 0.95–3.66,
P = 0.07), similar to that of SCS patients [
14]. Adverse outcomes, such as myocardial infarction are a safety indicator and should not be confused with efficacy indicators because this can camouflage treatment differences and add to an inappropriate procedural bias, as has occurred with the reporting of CREST-1 and other studies [
26,
42].