Understanding what this trial actually tested, why it matters, and how to interpret the results
Before we can understand CREST-2, we need to understand the landscape that created the question.
CEA reduced 5-year stroke risk from 11% to 5.1% vs medical therapy. But "medical therapy" meant aspirin and risk factor advice. No statins. No aggressive BP targets.
Confirmed CEA benefit in a larger European cohort. Again, medical therapy was rudimentary by today's standards.
Compared stenting to CEA head-to-head in symptomatic and asymptomatic patients. Found them roughly equivalent, but notably did NOT include a medical-therapy-alone arm.
High-intensity statins. PCSK9 inhibitors. Aggressive BP targets (<130 systolic). Better antiplatelet regimens. Smoking cessation programs. The question emerged: Do we still need to fix the artery?
If modern intensive medical management (IMM) has improved so dramatically, does adding CEA or stenting still provide meaningful benefit?
CREST-2 was designed to answer this directly.
This is the first critical point many people miss: CREST-2 was not one trial. It was two separate, parallel randomized trials.
patients randomized to
CAS + IMM vs IMM alone
patients randomized to
CEA + IMM vs IMM alone
A composite of:
This composite captures both the upfront risk of intervention AND the long-term stroke prevention benefit.
Some patients are anatomically suitable for stenting but not surgery (or vice versa). Randomizing between procedures would have excluded these patients. The parallel design allowed each procedure to be tested against modern medical therapy in its appropriate population.
This section is crucial for understanding generalizability. CREST-2 had extensive selection criteria for both operators and patients.
consecutive cases required
Combined stroke/death rate <3%
total cases required (25 consecutive within 5 years as primary operator)
Combined stroke/death rate <3%
Many stent operator applicants didn't have sufficient experience to apply for credentialing. The trial created a Companion Registry where operators could receive conditional approval to perform CAS procedures, building their case volume until they qualified for full credentialing.
This ensured procedures were performed by skilled operators at well-resourced sites, while allowing less experienced interventionalists a pathway into the trial.
Patients with these features could NOT be randomized to the stenting trial:
Both arms in both trials received identical intensive medical management. This wasn't "aspirin and a handshake" - it was aggressive, protocol-driven therapy.
| Component | Target |
|---|---|
| Antiplatelet therapy | Aspirin (325mg) + clopidogrel (or alternative) |
| LDL cholesterol | <70 mg/dL (high-intensity statin +/- ezetimibe) |
| Blood pressure | Systolic <140 mmHg (later revised to <130) |
| Diabetes management | HbA1c <7% if diabetic |
| Smoking cessation | Counseling and pharmacotherapy offered |
| Weight management | Diet and exercise counseling |
When we say "stenting beat medical therapy," we mean stenting beat this aggressive regimen. The comparison group wasn't left untreated - they received gold-standard preventive care.
The IMM results reflect what happens with attempted intensive management, not perfect adherence. Your clinic might actually achieve similar results.
Are your patients with asymptomatic carotid stenosis on aggressive medical therapy with regular follow-up and target monitoring?
If yes, these IMM results may be achievable. If they're on "a statin and aspirin" with no follow-up, you're not comparing apples to apples.
Here's what they found. We'll parse these carefully.
95% CI: 1.5 to 4.3
95% CI: 3.8 to 8.3
Absolute risk difference: 3.2 percentage points (95% CI: 0.6 to 5.9)
Relative risk: 2.13 (95% CI: 1.15 to 4.39)
P = 0.02 - Statistically significant
95% CI: 2.1 to 5.5
95% CI: 3.3 to 7.4
Absolute risk difference: 1.6 percentage points (95% CI: -1.1 to 4.3)
Relative risk: 1.43 (95% CI: 0.78 to 2.72)
P = 0.24 - Not statistically significant
A 95% confidence interval gives us a range of plausible values for the true effect. If the CI for a relative risk crosses 1.0, we can't confidently say the treatment is different from no effect.
Want to solidify your understanding of effect sizes and confidence intervals? → Module 3
Stenting showed significant benefit in:
All other subgroups showed no significant difference.
For CEA: No subgroup showed significant benefit when analyzed individually.
Caution: Subgroup analyses are exploratory and prone to false positives. These findings generate hypotheses but don't prove differential effects.
The protocol assumed these rates for power calculations:
| Arm | Expected | Actual |
|---|---|---|
| Revascularization | 3.6% (2.0% periprocedural + 1.6% late) |
CAS: 2.8% CEA: 3.7% |
| IMM Alone | 8.4% (for 85% power) |
6.0% (stenting trial) 5.3% (surgery trial) |
Medical therapy outperformed expectations. The IMM arm did 2-3% better than anticipated. This likely contributed to the difficulty in reaching significance, particularly for CEA's smaller effect size.
The composite endpoint combines periprocedural events (days 0-44) with late ipsilateral strokes. Let's separate these.
| Period | CAS + IMM | IMM Alone |
|---|---|---|
| Days 0-44 (periprocedural) |
7 strokes, 1 death = 8 events |
0 strokes, 0 deaths = 0 events |
| Beyond 44 days (late) |
7 ipsilateral strokes | 28 ipsilateral strokes |
Stenting caused 8 early events that wouldn't have happened with medical therapy alone. But it prevented 21 late strokes (28 - 7). The net benefit was 13 fewer events (21 prevented - 8 caused).
| Period | CEA + IMM | IMM Alone |
|---|---|---|
| Days 0-44 (periprocedural) |
9 strokes | 3 strokes |
| Beyond 44 days (late) |
10 ipsilateral strokes | 23 ipsilateral strokes |
CEA had 6 more early events than medical therapy (9 vs 3). It prevented 13 late strokes (23 - 10). The net benefit was 7 fewer events (13 - 6).
With a smaller net benefit, the trial didn't have sufficient power to detect this effect size.
When a trial has few events, significance can hinge on just a handful of outcomes. This is "statistical fragility."
Researchers calculate how many events would need to change to flip the result from significant to non-significant (or vice versa).
For the stenting trial:
This doesn't mean the finding is wrong. It means we should interpret it with appropriate humility. A single site with different outcomes, slightly different follow-up duration, or minor adjudication differences could affect the conclusion.
This distinction is essential for applying trial results to your patients.
"Can it work?"
Under ideal conditions: best operators, selected patients, rigorous protocols
"Does it work?"
In real-world conditions: average operators, typical patients, usual care
For CEA, the data suggest a trend toward fewer events, but the effect wasn't statistically clear in this trial. That doesn't erase the existing evidence from ACAS and ACST - it adds nuance. CEA likely still benefits some patients, but the magnitude of benefit over modern medical therapy may be smaller than we thought.
Apply what you've learned to interpret CREST-2 correctly.
CREST-2 randomized separately to CAS+IMM vs IMM and CEA+IMM vs IMM. These were not head-to-head comparisons of the procedures.
All operators required <3% complication rates. CAS operators needed a companion registry to build experience. 10 specific anatomic exclusions for stenting. This was an efficacy trial in ideal conditions.
2.8% vs 6.0% composite endpoint (p=0.02). The first trial to show intervention benefit over contemporary medical management.
3.7% vs 5.3% (p=0.24). Similar direction, smaller effect size, possibly underpowered.
Stenting had 8 early events vs 0 in medical therapy. The late stroke prevention (21 fewer) had to overcome this upfront cost.
The significance hinges on a small number of events. The direction is likely correct, but certainty is limited.
CREST-2 provides the first evidence that revascularization (specifically stenting) adds benefit to modern intensive medical therapy for asymptomatic carotid stenosis - but only in carefully selected patients treated by expert operators. Medical therapy alone remains reasonable for many patients.
You see an asymptomatic 65-year-old female with 70% carotid stenosis. Based on what you've learned, what would you offer her?