NON-CORONARY ARTERIAL DISEASE

D P Mikhailidis

BSc MSc MD FCPP FCP FFPM FRCP FRCPath

Academic Head

Dept. of Clinical Biochemistry (Vascular Disease Prevention Clinics)

Royal Free Hospital campus University College London

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec

DECLARATION OF INTEREST

• Lead: Guidelines for Medical Management of Carotid Artery Stenosis (Eur Soc Vasc Surg)

• Chair: Expert Panel on Small Dense Low Density Lipoprotein• Co-chair: Expert Panel on Post-Prandial Hypertriglyceridaemia• Executive Board member: International Atherosclerosis Society

(IAS), 2016-18

DECLARATION OF INTEREST

Editor-in-Chief of several journals, including: • Curr Med Res Opin• Expert Opin Pharmacother• Angiology• Curr Vasc Pharmacol • Open Cardiovasc Med J

CHD EQUIVALENTS

• Diabetes

• Peripheral arterial disease

• Symptomatic carotid disease

• Abdominal aortic aneurysm• Chronic kidney disease (eGFR <60 ml/min/1.73m2

• Rheumatoid arthritis (?psoriasis + arthritis, SLE)

Common Types of Non-Cardiac Vascular Disease

• Abdominal Aortic Aneurysms (AAA)

• Peripheral Arterial Disease (PAD)

• Carotid Artery Disease

• Atherosclerotic Renal Artery Disease (ARAS)

NON-CARDIAC VASCULAR DISEASE

• PLATELETS

• LIPIDS

• HYPERTENSION

• SMOKING

• DIABETES

PERIPHERAL ARTERIAL DISEASE

PAD and the risk of vascular events, death and amputation

Ouriel K. Lancet 2001; 358: 1257-64

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Time (years)

Patie

nts

(%)

Survival

Myocardial Infarction Intervention

Amputation

Causes of death: • 55% coronary artery disease• 10% cerebrovascular disease• 25% non-vascular• < 10% other vascular

Risk of death in PAD

*Kaplan-Meier survival curves based on mortality from all causes. Large-vessel PAD

Normal subjects

Asymptomatic PAD†

Symptomatic PAD†

Severe symptomatic PAD†

100

75

50

25

00 2 4 6 8 10 12

Surv

ival

(% o

f pat

ient

s)

Year

Criqui MH et al. N Engl J Med 1992; 326: 381-86

PAD and high risk of MI and strokeIncreased risk of MI* Increased risk of stroke*

PAD

Post-MI

Post-stroke

4 greater risk4

(includes only fatal MI and other CHD death)

5-7 greater risk1

(includes death)

2-3 greater risk2

(includes anginaand sudden death†)

2-3 greater risk3

(includes TIA)

3-4 greater risk2

(includes TIA)

9 greater risk3

* Over 10 years vs the general population except for stroke following stroke which measures subsequent risk per year

† Sudden death defined as death documented within 1 h and attributed to CHD.

1. Adult Treatment Panel II. Circulation 1994; 89: 1333-14352. Kannel WB. J Cardiovasc Risk 1994; 1: 333-3393. Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857-8634. Criqui MH et al. N Engl J Med 1992; 326: 381-386

Resnick HE et al. Circulation 2004; 109: 733-9

ABI and risk of cardiovascular death

Baseline ABPI*

Perc

ent (

%)

0

20

40

60

70

50

30

10

All-cause mortality

CVD mortality

*Mean participant follow-up 8.3 years

Platelet hyperactivity occurs in PAD patients evenif they are taking aspirin and/or after the additionof aspirin in vitro

Barradas MA, Stansby G, Hamilton G, Mikhailidis DP. Diminishedplatelet yield and enhanced platelet aggregability in platelet-richplasma of peripheral vascular disease patients. Int Angiol

1994;13:202-7

Robless PA, Okonko D, Lintott P, Mansfield AO, Mikhailidis DP, Stansby GP. Increased platelet aggregation and activation in peripheral arterial disease. Eur J Vasc Endovasc Surg 2003;25:16-22

Antiplatelet therapy reduces serious vascularevents and vascular death in patients with PAD.For infrainguinal arterial surgery or balloonangioplasty the benefit remains unproven, butthe number of trials to date is small

Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelettherapy for the prevention of myocardial infarction, stroke or vasculardeath in patients with peripheral vascular disease. Br J Surg 2001;88:787-800

For patients with PAD, the number sufferinga non-fatal MI, non-fatal stroke or vascular death in the antiplatelet group was decreased:

OR = 0.78; 95% CI = 0.63 - 0.96; p = 0.02

Effect of Antiplatelet Therapy on Vascular events* in PAD

Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86

% odds reduction

Intermittent claudication

Peripheral grafting

Peripheral angioplasty

All trials in PAD 23% ± 8

All trials 22% ± 2

1.00.50.0 1.5 2.0

Control betterAntiplatelet better

*Vascular events = MI, stroke or vascular death

PAD results in CAPRIE

PAD subgroup:Clopidogrel, n = 3,223; Aspirin, n = 3,229

Relative Risk Reduction = 23.8% (8.9 –36.2), p = 0.0028 over 1.9 years

MATCH trial Highlights

• Clopidogrel alone was as effective as clopidogrel + aspirin in the prevention of a combined endpoint in patients at high risk of stroke

• Combination therapy was associated with more bleeding

ASPIRIN IN PAD?

• POPADAD trial: no benefit of aspirin therapy in patients with diabetes and asymptomatic PAD (Belch J et al. BMJ 2008;331:a1840).

ASPIRIN IN PAD?• Meta-analysis: 18 randomized controlled

trials of aspirin with and without dipyridamole involving 5269 patients with PAD. A 12% reduction in MI, stroke, and cardiovascular death. There was a significant reduction in the secondary outcome of nonfatal stroke, but no significant effect on other secondary end points.

• LIMITATIONS (ASA alone 25% ↓but NS; some had DM, relatively small n)

JAMA 2009;301:1909-1919, 1927-28

WHY BOTHER WITH LIPIDS IN PAD?

HIGH RISK PATIENTS (MI,CVA,ARAS)

• Improving symptoms• Decreasing the risk of events• Preventing PAD?

Heart Protection Study

Patient Population:

20,536 patients

CHD(n=13,379)

Peripheral or

CerebrovascularDisease(n=10,036)

Diabetes Mellitus(n=5,963)

TreatedHypertension

(n=8,455)

SIMVASTATIN 40 mg: VASCULAR EVENT by PRIOR DISEASE

Risk ratio and 95% CISIMVASTATIN PLACEBOBaselinefeature (10269) (10267) STATIN better STATIN worse

STATIN worse

Previous MI 1007 1255

Other CHD (not MI) 452 597

No prior CHD

CVD 182 215

PVD 332 427Diabetes 279 369

ALL PATIENTS 2042 2606(19.9%) (25.4%)

24%SE 2.6reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN 40 mg:STROKE by AETIOLOGY

Risk ratio and 95% CISTATIN PLACEBOStrokeaetiology (10269) (10267) STATIN better STATIN worse

Ischaemic 242 376

Haemorrhagic 45 53

Subarachnoid 12 10

Unknown 69 100

Unadjudicated 136 146

ALL STROKE 456 613(4.4%) (6.0%)

27% SE 5.3reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Transient Ischaemic Attacks (TIA)

• 204 vs 250 (p = 0.02)

TIAs are ischaemic events that predict an increased risk of stroke.

Non-Coronary revascularization

450 vs 532 (p= 0.006)

• Carotid endarterectomy/angioplasty:

42 vs 82 (p= 0.0003)*

* included in non-coronary revasc.

LIMB SALVAGE• Patients were selected from 2007 - 2008 Medicare claims using the

International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes for claudication (n = 8128), rest pain (n = 3056), and ulceration/gangrene (n = 11,770) and Current Procedural Terminology codes for endovascular revascularization (n = 14,353) and open surgery (n = 8601).

• Half (n = 11,687) were statin users before revascularization. Statin users compared with non-users had lower amputation rates at 30 days (11.5 vs

14.4%; p < 0.0001), 90 days (15.5 vs 19.3%; p < 0.0001) and 1 year (20.9 vs

25.6%; p < 0.0001). • Survival analysis: improved limb salvage during 1 year for statin users vs

non-users for the diagnosis of claudication (p = 0.003), a similar trend for rest pain (p = 0.061) and no improvement for ulceration/gangrene (p = 0.65).

Vogel TR, et al. Preoperative statins and limb salvage after lower extremity revascularization in the Medicare population. Circ Cardiovasc Interv 2013; 6:694 - 700

LIMB SALVAGE AND EVENTS

• After propensity weighting, statin therapy was associated with lower 1 year rates of MACCE (stroke, MI or death; HR: 0.53; 95% CI: 0.28 to 0.99), mortality (HR: 0.49, 95% CI: 0.24 to 0.97) and major amputation or death (HR: 0.53, 95% CI: 0.35 to 0.98).

• Statin use was also associated with improved lesion patency among patients undergoing infrapopliteal angioplasty.

• Patients with LDL-C >130 mg/dl had increased HRs of MACCEand mortality vs those with lower levels of LDL-C.

Westin GG, et al. Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival in patients with critical limb ischemia. J Am Coll Cardiol 2014; 63: 682 - 90

LIMB SALVAGE AND EVENTS

• A total of 5861 patients with symptomatic PAD were included. • Statin use at baseline was 62.2%. • Patients on statins had a significantly lower risk of the primary adverse

limb outcome at 4 years vs those not taking statins [22.0 vs 26.2%; HR, 0.82; 95% CI, 0.72 - 0.92; p = 0.0013].

• The composite of cardiovascular death/myocardial infarction/stroke was similarly reduced (HR, 0.83; 95% CI, 0.73 - 0.96; p = 0.01).

Kumbhani DJ, et al.; REACH Registry Investigators. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J 2014; 35: 2864 - 72

LIMB SALVAGE AND EVENTS

• Vascular Study Group of New England registry: 2067 patients (71% male; mean age, 67 ± 11 years; 67% with critical limb ischemia [CLI]) who underwent infrainguinal bypass from 2003 to 2011.

• 1537 (74%) were on statins perioperatively and at 1 year follow-up and 530 received no statin.

• Crude, adjusted, and propensity-matched rates of 5 year surviva1, 1 year amputation, graft occlusion and perioperative MI.

Suckow BD, et al; Vascular Study Group of New England. Statin therapy after infrainguinal bypass surgery for critical limb ischemia is associated with improved 5-year survival. J Vasc Surg 2015; 61: 126 - 33

LIMB SALVAGE AND EVENTS

• Patients taking statins at the time of surgery and at the 1 year follow-up were more likely to have CHD (38 vs 22%; p < .001), DM (51 vs 36%; p < .001), hypertension (89 vs 77%; p < .001) and prior revascularization (50 vs

38%; p < .001). • Despite higher comorbidity burdens, long-term survival was better for those

taking statins: crude (RR 0.7; p < .001) and adjusted (HR 0.7; p = .001). • In subgroup analysis, a survival advantage was evident in patients on statins

with CLI (5 year survival rate, 63 vs 54%; log-rank, p = .01) but not claudication (5 year survival rate, 84 vs 80%; log-rank, p = .59).

• Statin therapy was not associated with 1-year rates of major amputation (12 vs 11%; p = .84) or graft occlusion (20 vs 18%; p = .58) in CLI patients.

• Perioperative MI occurred more frequently in patients on a statin in crude analysis (RR, 2.2; p = .01) but not in the matched cohort (RR, 1.9; p = .17).

Suckow BD, et al; Vascular Study Group of New England. Statin therapy after infrainguinal bypass surgery for critical limb ischemia is associated with improved 5-year survival. J Vasc Surg 2015; 61: 126 - 33

LIMB SALVAGE AND EVENTS

• Meta-analysis: 12 observational cohort studies and 2 randomised trials: 19,368 PAD patients.

• Statin therapy was associated with reduced all-cause mortality (OR 0.60, 95% CI 0.46 - 0.78) and incidence of stroke (OR 0.77, 95% CI 0.67 - 0.89).

• A trend towards improved CV mortality (OR 0.62, 95% CI 0.35 - 1.11), MI (OR 0.62, 95% CI 0.38 - 1.01) and the composite of death/MI/stroke (OR 0.91, 95% CI 0.81 - 1.03) was identified.

• Meta-analyses of studies performing adjustments showed decreased all-cause mortality in statin users (HR 0.77, 95% CI 0.68 - 0.86).

Antoniou GA, et al. Statin therapy in lower limb peripheral arterial disease: Systematic review and meta-analysis. Vascul Pharmacol 2014; 63: 79 - 87

STATINS, PAD AND EVENTS• In the Incremental Decrease in End Points Through Aggressive Lipid

Lowering (IDEAL) trial, 8888 MI patients were randomised to high-dose or usual-dose statin therapy (atorvastatin 80 vs simvastatin 20-40 mg/day).

• During a median follow-up of 4.8 years, 94 patients (2.2%) receiving atorvastatin and 135 patients (3.2%) receiving simvastatin developed PAD (HR = 0.70, 95% CI 0.53 - 0.91; p = 0.007).

• In PAD patients, major coronary events occurred in fewer patients in the atorvastatin group (14.4%) than in the simvastatin group (20.1%), but the difference did not reach significance (HR = 0.68, 95% CI 0.41 - 1.11; p = 0.13).

• Atorvastatin treatment significantly reduced overall CV (p = 0.046) and coronary events (p=0.004) and coronary revascularisation (p = 0.007) in these patients.

Stoekenbroek RM, et al.; Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin is superior to moderate-dose simvastatin in preventing peripheral arterial disease. Heart

2015; 101: 356 - 62

PADSMOKING

• Most powerful predictor of PAD• Major vascular risk factor• Major risk factor for erectile

dysfunction

PADSMOKING

• Smoking decreases the effectiveness of statins

• In some studies (e.g. pravastatin), the non-smoking placebo group had the same risk as the smoking treated group

Rizos E, Mikhailidis DP. Angiology 2001; 52: 575 - 87

Smoking and Biochemical and Haematological Variables

• HDL↓ TG↑• Insulin resistance↑• Bilirubin↓• Fibrinogen ↑• White Cell Count ↑

Katsiki N, Papadopoulou SK, Fachantidou AI, Mikhailidis DP. Smoking and vascular risk: are all forms of smoking harmful to all types of vascular disease?Public Health 2013;127:435-41.

PADHYPERTENSION

• Common in PAD• ? accompanied by microalbuminuria

• PAD is the third risk factor for stroke (after age and hypertension)

PADHYPERTENSION

• Aggressive treatment• > 1 drug often needed – adherence

(compliance) • 24h control is essential • Benefit in PAD (e.g. HOPE trial)

HYPERTENSION•Special advantages?

•Specific disadvantages?•Systolic, diastolic or central BP?

•Target Organ Damage (TOD)• Arterial stiffness; pulse wave velocity

•24 h ABPM (dipping, spiking)

PADHYPERTENSION

Amlodipine + perindopril = less new PAD compared with atenolol and bendroflumethiazide(35%; p = 0.0001)

ASCOT-BPLA Lancet 2005; 366:895-906

PADDIABETES

• PAD is common among type 2 diabetic patients - always check both ways!

• Amputations• ABI• Hypertension and lipids are more

important than glycaemic control for macrovascular complications

Risk Factors for PAD: Diabetes

• NHANES 1999-2002 (n = 5083)1

– In bivariate analysis stratified by age, DM is associated with an OR for PAD of 1.86 among subjects aged 60 years and older (p = 0.004)

• Framingham Heart Study (n = 5209)2

– DM associated with OR of 2.6 for development of intermittent claudication (IC) (p = 0.0001)

1. Lane JS, et al. J Vasc Surg 2006; 44: 319 - 242. Murabito JM, et al. Circulation 1997; 96: 44 - 9

Risk Reduction: Diabetes (DM)• Aggressive treatment of glycaemia in DM

– Not definitively shown to decrease CVD risk of patients with DM and PAD1

– DCCT (type 1 DM): reduced risk for lower-extremity macrovascular events by 22%; not significant2

– UKPDS (type 2 DM): reduced MI risk by 16%; not significant3

• Meticulous foot care essential to reduce risk for ulceration, gangrene and amputation1

DCCT = Diabetes Control and Complications Trial; UKPDS = United Kingdom Prospective Diabetes Study; ADA = American Diabetes Association

1. Hirsch AT, et al. Circulation 2006; 113: e463-654 2. DCCT Investigators. Am J Cardiol 1995; 75: 894-9033. UKPDS Group. Lancet 1998; 352: 837-53

ASSESSING PAD IN DIABETES

• Audible Doppler waveform• Ankle-brachial pressures (ABI)• Toe:brachial index (TBI) • Transcutaneous pressure of oxygen (TcPO2) • Pulse reappearance time (PRT)• Pulse oximetry (measures O2 saturation of blood)

NB why not angiography?

ASSESSING PAD IN DIABETES

• No ideal method. ABI is affected by calcification of the arteries (non-compressible). ABI is also affected by diabetic neuropathy.

• ABI after exercise? TBI?

Brownrigg JR, et al.; International Working Group on the Diabetic Foot (IWGDF). Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev 2015 Sep 5. [Epub ahead of print]

DM and PAD

• Using the ABI, the prevalence of PAD in patients with DM >40 years of age is ~20%. This increases to 29% in those >50 years of age.

• Severity and duration of DM are important predictors of both the incidence and the extent of PAD.

• In the UK Prospective Diabetes Study, each 1% increase in HbA1c correlated with a 28% increase in incidence of PAD, and higher rates of death, microvascular complications and major amputation. This correlation is particularly strong in men with hypertension or active tobacco use.

• Patients with PAD + DM tend to stay longer in hospital, incur greater costs, and account for greater use of hospital resources compared with patients with PAD alone.

DM and PAD

• 3406 patients (mean age: 71.7± 11.8 years, 61% male).

• Significant association of age (OR 1.67, 95%CI 1.53-1.82, p < 0.001), male gender (OR 1.23, 95%CI 1.04-1.47, p = 0.016), DM (OR 1.99, 95%CI 1.68-2.36, p < 0.001) andrenal insufficiency (OR 1.62, 95%CI 1.35-1.96, p < 0.001) with the likelihood of critical limb ischaemia (CLI).

Wyss TR, et al. Impact of cardiovascular risk factors on severity of peripheral artery disease. Atherosclerosis 2015; 242: 97 - 101

DM and PAD

• Hoorn study: glucose intolerance was associated with 20.9% prevalence of an ABI <0.9, relative to 7% in those with normal glucose tolerance

Beks PJ, et al. Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study. Diabetologia 1995; 38: 86 - 96

Metabolic Syndrome and PAD

• Several associations have been reported between vascular disease and metabolic syndrome (MetS)

Katsiki N, Athyros VG, Karagiannis A, Mikhailidis. Metabolic syndrome and non-cardiac vascular diseases: an update from human studies. Curr Pharm Des 2014; 20: 4944 – 52

• MetS and PAD in the National Health and Nutrition Examination Survey (1999-2004):

PAD prevalence in those with MetS was 7.0% compared with 3.3% in those without MetS. A total of 38% of the population with PAD had MetS.

Sumner AD, Khalil YK, Reed JF 3rd. The relationship of peripheral arterial disease and metabolic syndrome prevalence in asymptomatic US adults 40 years and older: results from the National Health and Nutrition Examination Survey (1999-2004). J Clin Hypertens (Greenwich) 2012; 14: 144 - 8

Obesity and PAD

Not a straightforward relationship. May be influencd by several factors (e.g. smoking status, quality of life, co-morbidities and age). Could be a U or J shaped relationship.

Ix JH, et al. Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study. Am J Epidemiol 2011; 174: 1036 - 43

Kato J. Obesity paradox in peripheral vascular disease. Atherosclerosis 2013; 229: 509 -10

Obesity and PAD

Overlap with:Obstructive Apnoea Syndrome (OSA)Non-Alcoholic Fatty Liver Disease (NAFLD)Epicardial fatRelease of adipokines from visceral fat

JS Berger, WR Hiatt

Medical Therapy in Peripheral ArteryDisease

Circulation 2012; 126: 491-500

0 1 2 3 4 5 6

INTERMITTENT CLAUDICATION*

*A post-hoc analysis of 4SAdapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.

New or Worsening Intermittent Claudication

38%risk reduction

P=0.008

4.54.03.53.02.52.01.51.00.5

0

%of

patie

nts

Simvastatin

Placebo

Years

MM McDermott et al. Circulation 2003;107:757

• Superior leg functioning after statin

• Independent of cholesterol lowering

PAD and INFLAMMATION

• Raised CRP in PAD• CRP predicts events in healthy subjects

or patients with vascular disease. Even if lipids are normal

Ridker PM et al. N Engl J Med 2005; 352: 20-28

Cumulative Incidence of Recurrent Myocardial Infarction or Death from Coronary Causes, According to the Achieved Levels of Both LDL Cholesterol and CRP

CAROTID ARTERY DISEASE

Statin pre-treatment• Among TIA + carotid patients, nonprocedural 7-day stroke

risk was 3.8% (CI, 1.2-9.7%) with statin treatment at TIA onset, compared with 13.2% (CI, 8.5-19.8%) in those not statin pre-treated (p = 0.01; 90-day risks 8.9 vs 20.8% [p = 0.01]).

• Statin pre-treatment was associated with reduced stroke risk in patients with carotid stenosis (OR for 90-day stroke, 0.37; CI, 0.17-0.82) but not non-stenosis patients (OR, 1.3; CI, 0.8-2.24; p for interaction, 0.008).

• On multivariable logistic regression, the association remained.

Merwick Á, et al. Stroke 2013; 44: 2814 - 20

Statin pre-treatment• 156 patients randomized to either a 600 mg (n = 78) or 300 mg (n =

78) clopidogrel load 6 h before carotid intervention and either atorvastatin reload (n = 76; 80 and 40 mg, 12 h and 2 h before the procedure, respectively) or no statin reload (n = 80).

• Primary endpoint: 30-day incidence of TIA/stroke or new ischemic lesions on cerebral diffusion-weighted MRI at 24 to 48 h.

• Patients were already on a statin at randomisation. • The primary outcome was significantly lower in the 600 mg

clopidogrel arm (18 vs 35.9% in the 300 mg group; p = 0.019) and in the atorvastatin reload arm (18.4 vs 35.0% in the no statin reload group; p = 0.031).

• High-dose clopidogrel also significantly reduced the TIA/stroke rate at 30 days (0 vs 9%, p = 0.02,) without increased bleeding risk.

Patti G et al. J Am Coll Cardiol 2013;61:1379-87•

STATINS AND OPERATIVE CARDIAC MORTALITY

• Decreased operative mortality associated with general and vascular surgery

• Benefit evident even after short-term use of statins

Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Eur J Vasc

Endovasc Surg 2006;32:286 - 93 Paraskevas KI, Veith FJ, Liapis CD, Mikhailidis DP. Curr Vasc Pharmacol

2013;11:112 - 20

STATINS AND OPERATIVE CARDIAC MORTALITY

• Pre-interventional use of statins has a protective effect against peri-interventional stroke, MI, or death in patients with internal carotid artery stenosis treated with stent-angioplasty (n = 344)

• Reiff T, et al. Eur J Vasc Endovasc Surg 2014;48:626 - 32

• Pre-interventional use of statins not only reduce cardiovascular events and mortality but may also have an important effect on the anatomic durability of CEA.

• Avgerinos ED, et al. Curr Vasc Pharmacol 2015;13:239 - 47

LIPIDS AND CAROTID STENTING (CAS)

• 127 patients without preprocedural statin treatment and 53 patients with preprocedural statin treatment.

•• Preprocedural statin therapy appears to reduce the

incidence of stroke, myocardial infarction, and death within 30 days after CAS.

Groschel K, et al. Radiology 2006;240:145-51

LIPIDS, CAROTID ENDARTERECTOMY AND ANATOMICAL DURABILITY

LIPID LOWERING DRUGS, protective for:• Early restenosis: OR = 0.601 (p< 0.007)• Early and late anatomical failure: OR = 0.517

(p< 0.03) and 0.128 (p< 0.0003) • Progression of disease: OR = 0.202 (p<

0.0002)

LaMuraglia GM et al. J Vasc Surg 2005; 41: 762-8

LIPID LOWERING TREATMENT AND CAROTID PLAQUE COMPOSITION

• Less lipid content (p <0.05)• Less oxidized LDL immunoreactivity (p <0.001)• Fewer macrophages (p <0.05)• Fewer T cells (p <0.05)• Less matrix metalloproteinase 2 immunoreactivity (p

<0.05)• Greater tissue inhibitor of metalloproteinase 1(TIMP

1) immunoreactivity (p <0.05)• Higher collagen content (p <0.005)

Crisby M et al. Circulation 2001; 103: 926-33

STATINS AND CAROTID PLAQUE COMPOSITION

• 240 symptomatic plaques (previous 10 days) were divided into 3 groups: 80 in group A (atorvastatin 80 mg), 80 in group B (atorvastatin 40 mg) and 80 to group C (no atorvastatin)

• Gray-scale median (GSM) score increased significantly more (at 12 months) in group A than in group B (48.65 vs 39.46, p < .02) and group C (48.65 vs 19.3, p = .0002)

• An inverse association between reduction of LDL-C and the increase in the GSM score (r = - 0.456, p = 0.007) was observed

• The reduction in hsCRP correlated inversely with the increase in GSM (r = - 0.398, p = 0.021)

Marchione P et al. J Stroke Cerebrovasc Dis 2015;24:138-43

INTENSIVE LDL-C LOWERING

Intensive lipid-lowering therapy reduced progression of cIMT in high-risk Japanese patients.

Yokoi H et al. Int Heart J 2014;55:146 - 52

INTENSIVE LDL-C LOWERING

• The combination of atorvastatin + ezetimibe canfurther decrease LDL-C and hsCRP levels and haveeffects on the progression of carotid atherosclerosisin elderly patients with hypercholesterolemiacompared with atorvastatin monotherapy

Luo P, et al. Genet Mol Res 2014;13:2377 - 84• Comment in• Genet Mol Res 2014;13:4805 - 7

DIABETES• Diabetic patients not on statins had 4 times

more deaths (8.5 vs 2.3%) and twice as many strokes/deaths (10.2 vs 5.3%) compared with those on statins.

• 500 CEAs followed retrospectively for 4 years• Statins had no effect on post-CEA restenosis

AbuRahma AF et al. J Am Coll Surg 2015;220:481-7

PLATELETS

• Which agent? • What to do when you use antiplatelet

agents and the patient will undergo surgery (including EVAR or CAS)?

• DES coronary stent problem

PLATELETS• Asymptomatic Carotid Emboli Study (ACES)

prospective study• 477 patients with asymptomatic carotid stenosis

followed-up for 2 years• Antiplatelet agents (p < 0.0001) and antihypertensives

(p < 0.0001) were independent predictors of lower risk of any stroke or cardiovascular death.

King A et al. Stroke 2013;44:542 - 6

ESVS GUIDELINES

Liapis CD, Bell PF, Mikhailidis DP, Sivenius J, Nicolaides A, Fernandes e Fernandes J, Biasi G, Norgren L; ESVS Guidelines Collaborators; European Society for Vascular Surgery. ESVS Guidelines: Section A--prevention in patients with carotid stenosis. Curr Vasc Pharmacol 2010;8:673-81

Liapis CD, Bell PF, Mikhailidis DP, Sivenius J, Nicolaides A, Fernandes e Fernandes J, Biasi G, Norgren L; ESVS Guidlines Collaborators; European Society for Vascular Surgery. ESVS Guidelines: Section B - diagnosis and investigation of patients with carotid stenosis. Curr Vasc Pharmacol

2010;8:682-91

Liapis CD, Bell PR, Mikhailidis D, Sivenius J, Nicolaides A, Fernandes e Fernandes J, Biasi G, Norgren L; ESVS Guidelines Collaborators. ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg 2009;37(4 Suppl):1-19

CAROTID STENOSIS AND MORTALITY

• Asymptomatic carotid stenosis (ACS) > 50%

• 17 studies reporting 5-year all-cause mortality in 11,391 patients with ACS

• Of the 930 deaths, 589 (62.9%; 95% CI 58.81-66.89) were cardiac-related. Average cardiac-related mortality of 2.9% per year

• All-cause and cardiac mortality in ACS patients are very high

• Giannopoulos A et al. Eur J Vasc Endovasc Surg 2015 Aug 20. pii: S1078-5884(15)00545-6. [Epub ahead of print]

High-Dose Atorvastatin after Stroke or Transient Ischemic Attack

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators

N Engl J Med 2006; 355: 549-59

Kaplan-Meier Curves for Stroke and TIA

SPARCL. N Engl J Med 2006;355:549-59

Kaplan-Meier Curves for Coronary and Cardiovascular Events

SPARCL. N Engl J Med 2006;355:549-59

RISK FACTOR ANALYSIS IN SPARCL

• Optimal control: LDL-C <70 mg/dl, HDL-C >50 mg/dl, TG <150 mg/dl and SBP/DBP <120/80 mmHg.

• Risk of stroke decreased as control increased (HR [95% CI] 0.98 [0.76 to 1.27], 0.78 [0.61 to 0.99], 0.62[0.46 to 0.84], and 0.35 [0.13 to 0.96]) for those achieving control of 1, 2, 3, or 4 factors as compared with none, respectively.

Amarenco P et al. Stroke 2009; 40: 2486 - 92

DIABETES• Glycaemic status is associated with all grades

of carotid atherosclerosis.• From early signs (IMT), to intermediate

degrees (carotid plaques), to advance atherosclerosis (carotid stenosis)..

Mostaza JM et al. Atherosclerosis 2015;242:377 - 82

DIABETES• 500 CEAs followed retrospectively for 4 years• Diabetic patients not on statins had 4 times

more deaths (8.5 vs 2.3%) and twice as many strokes/deaths (10.2 vs 5.3%) compared with those on statins.

• Statins had no effect on post-CEA restenosis

AbuRahma AF et al. J Am Coll Surg 2015;220:481-7

PLATELETS• Asymptomatic Carotid Emboli Study (ACES)

prospective study• 477 patients with asymptomatic carotid stenosis

followed-up for 2 years• Antiplatelet agents (p < 0.0001) and antihypertensives

(p < 0.0001) were independent predictors of lower risk of any stroke or cardiovascular death.

King A et al. Stroke 2013;44:542 - 6

48%risk reduction

P=0.009

CAROTID BRUITS*

*A post-hoc analysis of 4SAdapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.

2.5

2.0

1.5

1.0

0.5

0

%of

patie

nts

Simvastatin

Placebo

Years0 1 2 3 4 5 6

CAROTID BRUITSMeta-analysis of 17,295 patients with 62 413.5 patient-years of follow-up.

MI in patients with carotid bruits was 3.69 (95% CI 2.97-5.40) per 100 patient-years compared with 1.86 (0.24-3.48) per 100 patient-years in those without bruits

Pickett CA et al. Lancet 2008; 371: 1587-94

CAROTID BRUITSYearly rates of cardiovascular (CV) death were higher in patients with bruits than in those without (2.85 [2.16 - 3.54] per 100 patient-years vs 1.11 [0.45-1.76] per 100 patient-years).

In 4 trials comparing patients with and without bruits,the OR for MI was 2.15 (1.67-2.78) and for CV death 2.27 (1.49-3.49).

Pickett CA et al. Lancet 2008; 371: 1587-94

CAROTID BRUITSAuscultation for carotid bruits in patients atrisk for heart disease could help select those who might benefit the most from an aggressive modification strategy for CV risk.

Paraskevas KI, et al. Neurol Res 2008;30:523-30Pickett CA et al. Lancet 2008; 371: 1587-94

STROKE PREDICTORS

• Age• BP• Peripheral Arterial Disease

Evidence that lipids also predict stroke

ARBITER STUDYCAROTID IMT:• No reduction in 12 months with

pravastatin 40 mg• Significant reduction after treatment with

atorvastatin 80 mg

ARBITER STUDY

ABDOMINAL AORTIC ANEURYSMS

STATINS AND AAA EXPANSION IN HUMANS

Second Manifestation of ARTerial disease (SMART) studyPatients using lipid-lowering drugs had a 1.2 mm/y (95% CI -2.34 to -0.060) lower AAAgrowth rate than nonusers.86 lipid lowering and 144 controls. Median follow up = 3.3 years.

Schlosser FJ, et al. J Vasc Surg 2008;47:1127-33

HOW COULD STATINS HELP PATIENTS WITH AAA?

• Less inflammationKajimoto K et al. Atherosclerosis 2009; 206: 505-11• Animal modelsAtorvastatin decreased AAA diameter (MMP-12, ICAM) independently of lipid levels. Early action (1 week)

SOCIETY FOR VASCULAR SURGERY

Statins may be considered to reduce the risk of AAA growth.

Level of recommendation: WeakQuality of evidence: Low

Chaikof EL, et al.; Society for Vascular Surgery. The care of patients with an abdominal aortic aneurysm: the Society for Vascular Surgery practice guidelines. J Vasc Surg 2009;50(4 Suppl):S2-49

SMOKING

• Most powerful predictor of PAD and AAA

• Major vascular risk factor

DIABETES• Diabetes does not predict AAA risk!!• Diabetes may actually decrease the risk of

developing an AAA!!• Diabetes may actually decrease the rate of

AAA expansion!!

PLATELETS

• Which agent? • What to do when you use antiplatelet

agents and the patient will undergo surgery (including EVAR)?

• DES coronary stent problem

ATHEROSCLEROTIC RENAL ARTERY DISEASE

(ARAS)

ARAS• Features:BP difficult to control, PAD, flash pulmonary oedema, femoral bruits and low eGFR

• Risk (or associated) factors:Lipids, hypertension, CHD, PAD

• Treatment:Open surgery, endovascular (stenting) and best medical therapy

Renal Function and PAD

• ARAS• Renal atherosclerosis• Diabetes• Cholesterol emboli

PAD AND RENAL FUNCTION

Evidence for improvement of impaired renal function with statins in PAD.

Youssef F, Gupta P, Mikhailidis DP, Hamilton G. Angiology 2005;56: 279 - 87

Youssef F, Gupta P, Seifalian AM, Myint F, Mikhailidis DP, Hamilton G. Angiology 2004; 55: 53 - 62

CONCLUSIONS

• Patients presenting to vascular surgeons are less aggressively treated, in terms of prevention measures, than patients with CHD presenting to cardiology departments

• Aggressive risk factor management may improve prognosis as well as symptoms in this high risk population

A professor is someone who talks in someone else’s sleep

WH Auden 1907 – 1973 English poet

I hope that I kept you awake!