Carotid revascularization in cad patients

1. CAROTID REVASCULIRSATION IN CORONARY
ARTERY DISEASE ,TRIALS
-Dipak Patade

2. PROBLEM
 The concomitance between coronary artery disease and carotid artery disease is known and well
documented. Cerebrovascular complications are among the most feared consequences after coronary
artery bypass graft surgery (CABG).
 However, it is a fact that, despite the screening methods for these conditions and the advances in
surgical treatment, little has been achieved in terms of reducing the risk of complications in the
perioperative period.
 Publications are scarce, being mostly composed of reports or case series.
 There is little agreement on the best initial therapeutic approach (myocardial versus carotid
revascularization) or the best technique to be used (surgery with or without extracorporeal circulation,
hybrid treatments, etc.)

3. PROBLEM
 State of advanced atherosclerosis
 patients also have a higher incidence of left main coronary disease and a reduced left
ventricular ejection fraction compared with patients who have isolated coronary heart
disease .
 This topic will focus mainly on coexistent coronary and extracranial carotid
atherosclerosis.
 Issues that will be discussed include the management of the patient with an
asymptomatic carotid stenosis undergoing CABG, the role of combined or staged CABG
and carotid revascularization in these patients, and which strategies will result in the
lowest operative morbidity and mortality.

4. INCIDENCE
 a new clinical stroke or transient ischemic attack (TIA) occurred in approximately
3 percent of patients. (Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia
Research Group and the Ischemia Research and Education Foundation Investigators.Roach GW, Kanchuger M, Mangano CM, Newman M,
Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C N Engl J Med. 1996;335(25):1857)
 data from large retrospective reports published in 2008 and 2011 suggested that the overall incidence of
perioperative stroke had declined to 1.6 percent (Incidence, topography, predictors and long-term survival
after stroke in patients undergoing coronary artery bypass grafting.Filsoufi F, Rahmanian PB, Castillo JG, Bronster D,
Adams DH ,Ann Thorac Surg. 2008 Mar;85(3):862-70. )
 a 2014 prospective study found a clinically apparent perioperative stroke rate of 3.1 percent (New brain
infarcts on magnetic resonance imaging after coronary artery bypass graft surgery: lesion patterns, mechanism, and
predictors.Nah HW, Lee JW, Chung CH, Choo SJ, Kwon SU, Kim JS, Warach S, Kang DW Ann Neurol. 2014;76(3):347)

5. Incidence, topography, predictors and long-term survival
after stroke in patients undergoing coronary artery bypass
grafting. The incidence of stroke was 1.6% (n = 48) and similar between conventional CABG (1.6%)
and off-pump CABG (1.4%).
I. Early stroke occurred in 25 patients (52%).
II. large embolic stroke in 25 (76%),
III. watershed in 5 (15%), and
IV. mixed pattern in 3 (9%).
V. Chronic ischemic changes were found in 17 patients.
 Multivariate analysis revealed extensive aortic calcification (odds ratio [OR], 4.2), previous
stroke (OR, 2.2), female sex (OR, 1.9), and congestive heart failure (OR, 2.6) as predictors
of stroke.
 The hospital mortality rate after stroke was 16.7% (n = 8) compared with 1.5% (n = 44) in
those without (p<0.001).

6. Incidence, topography, predictors and long-term
survival after stroke in patients undergoing coronary
artery bypass grafting.
 The mortality rate was higher in early stroke at 24% (6 of 25) compared with 9%
(2 of 23) in late stroke.
 10-fold higher hospital mortality rates in patients who suffered a perioperative
stroke.
 Survival of stroke patients was 87% at 1 year and 62% at 5 years and was
significantly reduced compared with 96% and 85%, respectively, in patients without
stroke (p<0.001).

7. New brain infarcts on magnetic resonance imaging after
coronary artery bypass graft surgery: lesion patterns,
mechanism, and predictors
 Post-CABG new brain infarcts are mostly silent and cortically located.
 Old age, aortic arch atherosclerosis, use of cardiopulmonary bypass, and systemic
inflammatory response may contribute to the pathogenesis of post-CABG new brain infarcts.
 Radiographically-evident but clinically-silent strokes occur much more frequently.
 Approximately 40 percent of strokes occur intraoperatively and most of the remaining strokes
occur during the first 48 hours postoperatively.

8. The mechanisms of stroke in patients undergoing CABG:
 the most common mechanism is embolism:
 as changes in hemodynamics and aortic manipulation such as cross-clamping,
cannulation, and/or proximal graft anastomosis can cause embolization of thrombotic or atheromatous
debris from complex plaques in the ascending aorta .
 Atrial fibrillation is a common arrhythmia following CABG, occurring in 25 to 30 percent of patients, and
is a frequent cause of postoperative embolic stroke as well.
 large and small vessel occlusive disease and hypoperfusion.
 stenotic large artery can result in focal cerebral hypoperfusion, resulting in a watershed or borderzone
infarct between two cerebrovascular territories.
 Perioperative myocardial infarction (MI) and arterial dissection are also potential mechanisms of ischemic
stroke.
 The development of postsurgical systemic inflammatory response and the withholding of antithrombotic
therapy in the perioperative period are potential risk factors for ischemic stroke.

9. Strokes after cardiac surgery and relationship to carotid stenosis.Li Y, Walicki D,
Mathiesen C, Jenny D, Li Q, Isayev Y, Reed JF 3rd, Castaldo JE .Arch Neurol.
2009;66(9):1091
 total =4335 patients
 incidence -1.8%
 Only 5.3% of these strokes were of the large-vessel type, and most strokes (76.3%) occurred without
significant carotid stenosis
 In 60.0% of cases, strokes identified via computed tomographic head scans were not confined to a
single carotid artery territory
 in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis
 75 percent were due to a cardioembolic source (aortic arch atherosclerosis or atrial fibrillation), 13
percent small-vessel disease, and 5 percent large artery stenosis, including carotid artery disease.
 Undergoing combined carotid and cardiac operations increases the risk of postoperative stroke compared
with patients with a similar degree of carotid stenosis but who underwent cardiac surgery alone (15.1% vs
0%; P = .004)

10. Risk factors:
1)Patient characteristics:
•Moderate to severe atherosclerosis of
ascending aorta
• Atrial fibrillation
•Prior stroke or TIA
•Subcortical small vessel disease
•Moderate to severe carotid stenosis
•Peripheral vascular disease
•Diabetes
•Hypertension
•Pulmonary disease
•Heart failure
•Unstable angina
•Recent myocardial infarction
•Moderate to severe left ventricular
dysfunction
•Prior cardiac surgery
•Older age
•Female gender
•Elevated pulse pressure
•Tobacco use
•Chronic kidney disease

11. Risk factors:
2) Intraoperative features:
•Severe hypotension
•Manipulation of atherosclerotic aorta
•Cardiopulmonary bypass time greater
than two hours
•Use of intra-aortic balloon pump
Postoperative features:
• Atrial fibrillation
•Low cardiac output syndrome

12. Aortic atherosclerosis
 Atherosclerosis of the ascending aorta may be a more important cause of perioperative
stroke than carotid artery stenosis .
 In a study of over 900 patients undergoing cardiac surgery, the risk of perioperative stroke
among patient with and without significant atherosclerosis of the ascending aorta was 9
versus 2 percent, respectively.
 The risk depended on the presence, location and extent of the disease.
 Aortic atheromas that are large (≥5 mm thick) or mobile carry a higher risk of stroke.
( Postoperative stroke in cardiac surgery is related to the location and extent of
atherosclerotic disease in the ascending aorta.van der Linden J, Hadjinikolaou L, Bergman P,
Lindblom D .J Am Coll Cardiol. 2001;38(1):131)

13. Carotid stenosis
 The rate of stroke is elevated in patients with carotid stenosis who have CABG.
 unilateral asymptomatic carotid stenosis of 50 to 99 percent is not an independent risk
factor for ipsilateral ischemic stroke with CABG.
 In contrast, certain groups of patients with carotid artery disease appear to have an
increased risk of stroke with CABG, including the following:
Symptomatic carotid stenosis of 50 to 99 percent in men and 70 to 99
percent in women
Bilateral asymptomatic stenosis of 80 to 99 percent
Unilateral asymptomatic stenosis of 70 to 99 percent and contralateral
carotid occlusion

14. Stroke after cardiac surgery and its association with asymptomatic carotid disease: an updated
systematic review and meta-analysis.Naylor AR, Bown MJ .Eur J Vasc Endovasc Surg. 2011
May;41(5):607-24. Epub 2011 Mar 10]. A 2011 meta-analysis
 the risk of perioperative stroke after cardiac surgery was approximately 7 percent in those
with ≥50 percent carotid stenosis and 9 percent in those with ≥80 percent stenosis
 higher than the described rate of 1.6 to 3 percent in the general population undergoing
surgery
 The main stroke predictors were symptomatic carotid stenosis and bilateral
carotid stenosis/occlusion
 The presence of a recently symptomatic carotid artery stenosis probably increases the risk
of a postoperative stroke in patients undergoing CABG, but there are few data directly
addressing this question.

15.  In one study, 28 patients with prior symptomatic unilateral carotid disease did not undergo
prophylactic carotid endarterectomy, and ischemic stroke occurred in 4 (14 percent)
However, only one of the four strokes was attributed to ipsilateral carotid stenosis and was
therefore potentially preventable by prophylactic carotid revascularization. (Screening carotid
ultrasonography and risk factors for stroke in coronary artery surgery patients.D'Agostino RS, Svensson
LG, Neumann DJ, Balkhy HH, Williamson WA, Shahian DM .Ann Thorac Surg. 1996;62(6):1714)
 One retrospective study of patients with preoperative carotid duplex ultrasound having
CABG compared 117 patients who had severe asymptomatic carotid stenosis (≥75 percent)
with 761 patients who did not have severe carotid stenosis
 Patients with severe asymptomatic carotid artery stenosis do not have a higher risk of
stroke and mortality after coronary artery bypass surgery.
(Mahmoudi M, Hill PC, Xue Z, Torguson R, Ali G, Boyce SW, Bafi AS, Corso PJ, Waksman R .Stroke. 2011
Oct;42(10):2801-5. Epub 2011 Aug 4]. Both groups had similar rates of in-hospital stroke (3.4 versus 3.6) and
mortality (3.4 versus 4.2 percent).

16.  Since 2005, 4 studies have reported patients with asymptomatic carotid stenosis of 70 to 99 percent (n = 156) or 50 to 99
percent (n = 42) who did not have prophylactic carotid revascularization; the rate of perioperative stroke with CABG in these
patients was 0 percent.
 it remains controversial whether asymptomatic internal carotid artery stenosis is a major cause of stroke that would benefit from
revascularization, or
 is merely a surrogate stroke risk marker associated with multiple other potential stroke risk factors and mechanisms, in
which case carotid revascularization would be expected to have little or no benefit.
 it is plausible that characteristics of the carotid lesion, such as plaque morphology and the presence of downstream
microemboli on transcranial Doppler, may impact the risk of stroke.
1.Strokes after cardiac surgery and relationship to carotid stenosis.Li Y, Walicki D, Mathiesen C, Jenny D, Li Q,
Isayev Y, Reed JF 3rd, Castaldo JE .Arch Neurol. 2009;66(9):1091.
2.Managing patients with symptomatic coronary and carotid artery disease.Naylor AR .Perspect Vasc Surg
Endovasc Ther. 2010 Jun;22(2):70-6.
3.The influence of asymptomatic significant carotid disease on mortality and morbidity in patients undergoing
coronary artery bypass surgery.Ghosh J, Murray D, Khwaja N, Murphy MO, Walker MG .Eur J Vasc Endovasc
Surg. 2005 Jan;29(1):88-90.
4. Patients undergoing cardiac surgery with asymptomatic unilateral carotid stenoses have a low risk of peri-
operative stroke..Baiou D, Karageorge A, Spyt T, Naylor AR .Eur J Vasc Endovasc Surg. 2009 Nov;38(5):556-9.
Epub 2009 Aug 29.

18. Prevalence and predictors of carotid stenosis
●Diabetes
●Peripheral vascular disease
●Left main coronary artery stenosis ≥60 percent
●Carotid bruit
●Prior stroke or TIA (the most consistent predictor)
●Prior vascular operation
●Smoking
●Female gender
●Age

19. Prevention of stroke associated with carotid artery disease
and myocardial revascularization
 The early risk of stroke after myocardial revascularization is higher after CABG than after
PCI.
 After 30 days, stroke rates between revascularization techniques were similar in a recent
individual patient data meta-analysis of 11 randomized trials
(Head SJ, Milojevic M, Daemen J, Ahn JM, Boersma E, Christiansen EH, Domanski MJ,
Farkouh ME, Flather M, Fuster V, Hlatky MA, Holm NR, Hueb WA, Kamalesh M, Kim
YH, M€akikallio T, Mohr FW, Papageorgiou W, Park SJ, Rodriguez AE, Sabik III JF,
Stables RH, Stone GW, Serruys PW, Kappetein AP. Stroke rates following surgical
versus percutaneous coronary revascularization. J Am Coll Cardiol 2018;72:386–398.)

21. Stroke rates following surgical versus percutaneous
coronary revascularization. J Am Coll Cardiol
2018;72:386–398
 The metanalysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG
(n = 5,765) with a mean follow-up of 3.8 ± 1.4 years during which a total of 293 strokes
occurred.
 At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]:
0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001).
 At 5-year follow-up, stroke remained significantly lower after PCI than after CABG
(2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027).
 Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus
2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72).

22. Stroke rates following surgical versus percutaneous
coronary revascularization. J Am Coll Cardiol
2018;72:386–398 No significant interactions between treatment and baseline clinical or angiographic
variables for the 5-year rate of stroke were present, except for diabetic patients (PCI:
2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for
interaction = 0.004).
 Patients who experienced a stroke within 30 days of the procedure had significantly higher
5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001)
and CABG (41.5% vs. 8.9%, p < 0.001).
 This individual patient-data pooled analysis demonstrates that 5-year stroke rates are
significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the
30-day post-procedural period but a similar risk of stroke between 31 days and 5 years.
 The greater risk of stroke after CABG compared with PCI was confined to patients with
multivessel disease and diabetes.
 Five-year mortality was markedly higher for patients experiencing a stroke within
30 days after revascularization

23. Does preoperative carotid stenosis screening reduce perioperative stroke in patients
undergoing coronary artery bypass grafting? Masabni K, Raza S, Blackstone EH,
Gornik HL, Sabik JF III. J Thorac Cardiovasc Surg 2015;149:1253–1260.)
 clinical variables alone can identify those who have significant carotid artery disease with as high a
degree of sensitivity as ultrasound.
 However, low specificity would seem to dictate ultrasound screening, and possibly additional
confirmatory testing of a large proportion of these patients, to alleviate a false-positive diagnosis.
 carotid duplex ultrasound screening, whether selective or nonselective, identifies only a minority of
patients who will develop perioperative stroke, and intervening for those with carotid disease might
not decrease the risk of these neurologic events.
 Absence of a direct causal relationship between carotid artery stenosis and ipsilateral stroke, and the
increased morbidity associated with carotid revascularization, support the argument that prophylactic
carotid revascularization might be of no benefit in asymptomatic patients undergoing CABG.
 This area, then, is clearly in great need of further research

24. CAS or CEA?

25. CAS or CEA?
What is the evidence from the clinical trials
 CAVATAS
 WALLSTENT
 SAPHIRE
 SPACE
 EVA- 3S
 ICSS/CAVATAS-2
 CREST

26. CAVATAS Lancet. 2001
 First multicenter RCT comparing CEA and CAS.
 Stenting was rolled late into the trial.
 24 centers in Europe, Australia, and Canada enrolled 504 pts.
 High-risk surgical pts were excluded.
 Mixed symptomatic and asymptomatic pts.
 253/504 randomized to CEA and 251/504 to endovascular tx (65 received stents, 26%).
 No distal protection device.
 Results: No statistically significant difference between both arms in the rate of stroke, death or MI
within 30 days and 1-year stroke or death rates
 Encouraging results generated interest in CAS, and inspired more studies to be undertaken.

27. WALLSTENT Stroke. 2001
 First multicenter RCT in United States comparing CEA and CAS.
 Began in 1996, randomized 219 symptomatic pts (CS ≥ 60% within 120 days of sxs).
 Pts were not stratified according to their operative risk.
 All CAS arm 112/219 received stents without protection device.
 107/219 pts underwent CEA.
 Results: Stroke and death at 30 days and 1-year follow-up were significantly lower for CEA
vs CAS.
 Therefore, trial was prematurely stopped
 Concerns were raised about the lack of experience of the endovascular operators.

28. SAPPHIRE N Engl J Med 2004-2008
 First RCT comparing CEA with CAS using distal protection device.
 Multicenter, prospective, randomized trial based in United States set out to prove CAS with
distal protection was not inferior to CEA in patients at high risk for surgery.
 747 pts enrolled 2000-2002, asymptomatic CS ≥ 80% and symptomatic CS ≥ 50%.
 334/747 pts placed in the randomized arm, remaining 413 into either a stent or surgical
registry.
 Inclusion criteria (included symptomatic eligibility) and exclusion criteria

29. SAPPHIRE N Engl J Med 2004
 167/334 underwent CEA and 167/334 underwent CAS.
 No demographic or baseline medical history differences between groups; (71%)
asymptomatic and approximately 20% of pts > 80 yrs.
 Primary endpoint: death, stoke, and MI.
 30-day stroke/death/MI rates: CAS (4.8%) vs. CEA (9.8%) (P =.09).
 At 1 year, CAS (12.2%) suffered a stroke, MI, or death vs. CEA (20.1%) (noninferior analysis:
P =.048).
 In addition to achieving noninferiority, rates of target vessel revascularization and cranial
nerve palsy favored stenting.

30. SAPPHIRE N Engl J Med 2008
 Reported 3-year results data :334 pts , 86% CAS group and 70% CEA group.
 The prespecified major secondary endpoint at 3 yrs: composite of stroke death and MI
within 30 days or death or ipsilateral stroke 31-1080 days
 Not statistically different.
 Excluding MI within 30 days of the procedure and deaths from nonneurologic causes, the
3-year stroke, death, MI rate was 8.4% for CAS and 9.0% for CEA. Conclusion:
 Pts with severe CS and increased surgical risk, no significant difference could be shown in
long-term outcomes between patients who underwent CAS with embolic protection
device and those who underwent CEA.

31. SPACE Lancet 2006
 To establish noninferiority for CAS in symptomatic pts with CS ≥ 50% and with low surgical
risk.
 Multicenter randomized trial throughout Germany, Austria, and Switzerland.
 Primary endpoints were ipsilateral ischemic stroke or death from randomization to 30 days
post procedure. All patients received aspirin preprocedure.
 1200 pts randomized, 595 to CEA and 605 to CAS.
 At 30 days, ipsilateral stroke or death was not different,
 6.35% for CEA and 6.8% for CAS (P =.09).
 Distal protection used only in 27%; subgroup analysis showed no difference between pts
with cerebral protection and those without.
 Stroke 2009 The trial was stopped as result of interim analysis demonstrated that 2500
patients would be needed to reach significance and determine noninferiority of CAS given
the results up to that point. The SPACE steering committee acknowledged a lack of funds
to expand enrollment to 2500 and therefore suspended the trial..

32. EVA-3S .N Engl J Med 2006
 Similar to the SPACE trial, RCT designed to assess noninferiority of CAS versus CEA in low-
risk, symptomatic patients with CS ≥ 60%.
 Multicenter study conducted in France.
 Primary endpoint was 30-day stroke or death.
 The study was stopped after enrollment of 527 pts for reasons of safety and futility.
 Primary endpoint was 3.9% CEA vs. 9.6% CAS (P =.01).
 Protection devices was not required initially.
 Pts treated without protection had 25% rate of stroke or death at 30 days (5/20),
prompting protocol changes.
 CAS operators had unequal experience compared to surgeons performing CEA.

33. EVA-3S .N Engl J Med 2006
 Risk was 9.6% higher than other RCTs.
 The absolute risk increase of stenting was 5.7%, and for every 17 cases treated with CAS
rather than CEA, 1 additional stroke or death occurred at 30 days post procedure.
 The overall incidence of disabling stroke within 30 days was 3.4% for CAS, 1.5% for CEA.
 A significantly greater proportion of strokes occurred on the same day of the procedure in
the stenting group than in the surgical group (P =.05).
 Conclusion: Patients with symptomatic CS of ≥60%, CAS was inferior to CEA with respect
to the incidence of stroke and death at 30 days post procedure.

34. CREST Carotid Revascularization Endarterectomy versus Stenting Trial
 Prospective randomized CEA vs. CS as prevention of stroke in symptomatic and
asymptomatic patients
 Composite primary endpoint of any periprocedural stroke/MI/death OR ipsilateral stroke
on f/u
 n = 2502 17 centers North America (CEA 1240, CS 1262)
 Primary endpoint (CAS 7.2% vs. CEA 6.8%)
 Individual risks: 30 d. any stroke rate (CAS 4.1% vs. CEA 2.3%)

35. CREST Results
 Though Major strokes < 1% both groups
 Periprocedural MI (CAS 1.1% VS. CEA 2.3%)
 Ipsilateral stroke @ mean f/u (2.5y): (CAS 2.0% vs. CEA 2.4%)
 Cranial nerve palsy: (CAS 0.3% vs. CEA 4.8%)
 Age effect: > 69yr better outcome with CEA
 < 69yr better outcome with CAS
 Gender effect: No difference
 Symptoms effect: No difference

36. ICSS/CAVATAS-2 Lancet. 2010
 International Carotid Stenting Study:
 An interim analysis. CAS vs. CEA in patients with symptomatic carotid stenosis.
 Patients are low-risk equally suited for CAS or CEA
 Multicentre, international, randomized controlled trial
 The primary outcome: 3-year rate of fatal or disabling stroke in any territory, which
has not been analyzed yet.
 The main outcome measure for the interim safety analysis:120- day rate of stroke,
death, or procedural MI. Analysis was by intention to treat (ITT).
 1713 patients (CAS 855; CEA 858).

37. ICSS/CAVATAS-2 Lancet. 2010
 Disabling stroke or death: CAS 4.0% vs. CEA 3.2% (hazard ratio [HR] 1.28, 95% CI 0.77-
2.11).
 Stroke, death, or procedural MI: CAS 8.5% vs. CEA 5.2% (HR 1.69, 1.16-2.45, p=0.006).
 Risks of any stroke (CAS 65 vs CEA 35 events; HR 1.92, 1.27-2.89) and
 all-cause death (CAS 19 vs CEA 7 events; HR 2.76, 1.16-6.56)

39. 2017 ESC Guidelines on the Diagnosis and
Treatment of
Peripheral Arterial Diseases, in collaboration
with the European Society for
Vascular Surgery (ESVS)

55.  For patients undergoing CABG who are selected for carotid revascularization,
 guidelines suggest a combined procedure with carotid endarterectomy plus CABG, rather than a
staged procedure, for those who have severe left main coronary artery disease, diffuse coronary
heart disease without satisfactory collaterals, or unstable angina (Grade 2C).
 guidelines suggest a staged carotid revascularization with carotid endarterectomy or carotid artery
stenting before CABG, rather than a combined procedure, for patients with chronic stable angina in the
absence of a recent myocardial infarction (Grade 2C)
 For patients undergoing CABG who are selected for carotid revascularization, guidelines
recommend not employing carotid artery stenting immediately prior to CABG (Grade 1C) because
dual antiplatelet therapy is required following stenting, a factor that likely increases the perioperative risk
of bleeding with the CABG procedure.
 However, carotid stenting is an alternative to carotid endarterectomy if the CABG is not urgent. Such
patients could receive a carotid stent with antiplatelet therapy for several weeks, followed by CABG
surgery.

56. Timing of cardiac surgery after a stroke
 Timing of cardiac surgery after a stroke should include sufficient delay
 to allow identification of the cause of stroke,
 restoration of cerebral autoregulatory mechanisms, and
 remodeling of the parenchymal damage to minimize the risk of hemorrhagic
transformation.
 Unless emergent cardiac surgery is warranted -a delay of at least a month longer for
strokes involving larger territories.

57. Gaps in the evidence