1. John P. A. Ioannidis (age 50) Stanford School of Medicine, Athens Graduate, former chairman Department of Hygiene and Epidemiology, University of Ioannina School of Medicine
Proteus phenomenon is the greater tendency in science for early replications of a work to contradict the original findings, a consequence of publication bias..

2. High grade asymptomatic carotid stenosis: intervention vs medical treatment – what changes have there been between the 1990s and the 2010s?
Alison Halliday
Professor of Vascular Surgery
University of Oxford
LIVE, Ioannina, Greece, 27th May 2016

3. Medical treatments for Carotid stenosis
Blood Pressure 1990s target – 160/90mm Hg 2000s 2010s BP target 140/80 (or 120/80) Antithrombotic Treatments (including AF) Aspirin, warfarin, then some clopidogrel, NOACs Lipid-lowering Statins -None until late 1990s, common from 2000s, ubiquitous in the 2010s Fibrates, Ezetamibe, (injectable PCSK9 inhibitors (monoclonal abs))

4. Interventions for Carotid Stenosis
1990s - Carotid Surgery 2000s – surgery, (trials of stenting for mostly symptomatic disease were discouraging) 2010s - surgery or stenting

5. Q: What does CEA add to drug therapy?
Analysis: 5000 patients in ACST-1, ACAS and VACS randomised trials of immediate vs deferred CEA, analysed by ALLOCATED treatment (ITT analyses)
Almost all were on double, or on triple, drug therapy
(Double therapy: BP lowering + anti-thrombotic)
Triple therapy also includes a statin; does this so reduce risk that CEA is no longer worthwhile?
All three trials asked the same question: what does CEA add to drug therapy in patients who might be at risk of stroke from their tight carotid stenosis?
Over 5000 patient entered in the Veterans’ Trial, ACAS, and ACST-1 comparing immediate vs deferred CE were analysed by ALLOCATED treatment (in other words, by intention to treat)
Almost all were on double or on triple drug therapy… (read the rest)

6. in ACST-1, ACAS and VACS Trials
Methods
5,000 individual patients
in ACST-1, ACAS and VACS Trials
VACS
ACAS
ACST-1
Nos. of patients
(Immediate vs Deferred)
444
(211 vs 233)
1662
(828 vs 834)
3120
(1560 vs 1560)
Period of randomisation
Apr 83 – Oct 87
Dec 87 – Dec 93
Apr 93 – Jul 03
Date of last follow-up
May 1991
Feb 1997
May 2008
Median (IQR) follow-up year†
4.5 ( )
4.2 ( )
6.1 ( )
Median year of follow-up, as measured from the time of entry to that of the first stroke, death, loss to follow-up, or most recent examination

7. 10-year risk of any stroke or perioperative death
All trials, either with double or with triple drug therapy
A. Any stroke or perioperative death
B. Any non−perioperative stroke
In all 3 trials, those allocated CEA had a highly significant reduction in 5 and 10-year stroke risk; those in the ‘immediate CEA group’ in RED, had early hazard from operation, followed by a long-term reduction in stroke risk compared to those in the deferred group..
After any successful CEA (RIGHT-HAND GRAPH) the reduction in stroke risk is clear, by 5 years the ARR is 6.0% and this is maintained to 10 years (ARR 6.5%)

8. 10-year risk of any stroke or perioperative death
Only patients on triple (ie, including statin) therapy before event
A. Any stroke or perioperative death
B. Any non−perioperative stroke
In this ITT analysis, only patients who were on all three therapies (ie including LIPID-LOWERING) are shown.
Here again, on the LEFT, in the immediate surgery group, is the early hazard of surgery followed by a lower stroke risk. At 5 years the ARR (in other words, the ‘gain’ in strokes saved) is 2.7%, and by 10 years it is 5.5%
On the RIGHT, after successful CEA, the gain (or ARR) is 3.6% at 5 years and 6.1% at 10 years, a very significant reduction in risk

9. Non-perioperative stroke risk: includes lipid-lowering therapy before any stroke
CEA halves stroke rate whether or not statins are used
(& statins halve stroke rates whether or not CEA is done)
So CEA halves stroke risk whether or not statins are used, and the addition of lipid-lowering therapy further reduces stroke risk (including peri-operative stroke and myocardial infarction risk) by about half.
Here you can also see that the annual event rate ratio (whether on statins or not) is halved by CEA.
Importantly, for those on lipid-lowering therapy allocated surgery, the annual event rate was reduced from 1.5% per year, to 0.8%/year. For those not on Statins it was reduced from 3.4%/year to 1.9%/yr.

10. Statins work: With CEA or without CEA,
Summary: what does CEA add to drug therapy over the next 5-10 years after trial entry?
Statins work: With CEA or without CEA,
a statin approximately halves the stroke rate
And CEA works: With a statin or without a statin, CEA approximately halves annual stroke rate
Who benefits and which strokes are prevented?
So, back to our original question about stroke prevention – what does the addition of CEA add to drug treatment during the next 5-10 years?
Next – over to Alison (?) – who benefits and which types of stroke are prevented?

11. Non-perioperative stroke, by trial
Risks appear to have been halved in all three trials

12. Non-perioperative stroke, by sex Male and female risks are both halved

13. Non-perioperative stroke, by outcome
Fatal/disabling and non-disabling strokes are both halved

14. Non-perioperative stroke, by subtype
Ipsilateral and contralateral strokes are both reduced

15. Exploratory per-protocol analysis Data are censored by compliance
Immediate group:
at first stroke before CEA
at 1 year if no CEA within the first year
Deferred group:
at first non-symptomatic CEA

16. ACAS: 5−year allocated and actual use of CEA

17. ACST-1: 5−year allocated and actual use of CEA

18. 10-year risk of any stroke or perioperative death (ITT)
A. Any stroke or perioperative death
B. Any non−perioperative stroke

19. 10-year risk of any stroke or perioperative death (PP)
A. Any stroke or perioperative death
B. Any non−perioperative stroke
per-protocol analysis

20. 10-year risk of any stroke or perioperative death (ITT)
On lipid lowering therapy before stroke (mean age 67.6 years)
A. Any stroke or perioperative death
B. Any non−perioperative stroke

21. 10-year risk of any stroke or perioperative death (PP)
On lipid lowering therapy before stroke (mean age 67.6 years)
A. Any stroke or perioperative death
B. Any non−perioperative stroke
per-protocol analysis

22. Per-protocol analysis; actual CEA vs not Non-perioperative stroke

23. The proportional reduction is the same for fatal/disabling and for non-disabling strokes
The largest absolute effect is on ipsilateral strokes, but other strokes are also reduced
Risks are approximately halved for each of:
- Male or female, under-65 or (few were 75+)
- High or low BP/cholesterol/glucose (diabetes)
- Moderate/severe stenosis, previous symptoms
contralateral stenosis, echolucent

24. Asymptomatic carotid stenosis:
Even on anti-thrombotic, blood pressure lowering and lipid-lowering (triple) medical therapy -
successful CEA halves the stroke
rate over the next 5-10 years.

25. High grade asymptomatic carotid stenosis: intervention vs medical treatment – what changes have there been between the 1990s and the 2010s?
Medical treatments have improved…. But only statins have made a real impact on stroke risk For truly asymptomatic patients (no symptoms, no brain infarcts) annual stroke risk may now be less than 1.5%, but for patients with previous symptoms or with silent brain infarcts, it may well be 2% or more However, the risk of intervention has also halved and the decision to intervene depends on operator skill and on proper patient assessment before any intervention is undertaken.