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
CHD EQUIVALENTS
• Diabetes
• Peripheral arterial disease
• Symptomatic carotid disease
• Abdominal aortic aneurysm
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)
Potential CHD Equivalents
• Non-Alcoholic Fatty Liver Disease (NAFLD), especially NASH (Non-Alcoholic Steatohepatitis)
• Metabolic Syndrome, Impaired Fasting Glucose, Impaired Glucose Tolerance
• Obstructive Sleep Apnoea (OSAS)
• Erectile Dysfunction (ED)
• Periodontitis
• Chemotherapy (e.g. anthracyclines) and Radiotherapy (chest)
• Inflammatory Bowel Disease
CARDIOVASCULAR RISK
FACTORS
NON-MODIFIABLE
• Age
• Gender
• Family History
• Personal History
• Ethnicity
MODIFIABLE
• Lipids
• Smoking
• BP
• Diabetes / IGT
• Obesity / Diet
• Coagulation factors
• Homocysteine
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)
Pati
en
ts (
%)
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
0
0 2 4 6 8 10 12
Su
rviv
al
(% o
f p
ati
en
ts)
Year
Criqui MH et al. N Engl J Med 1992; 326: 381-86
PAD and high risk of MI and stroke
Increased 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 angina
and 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: 1333-1435 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333-339 3. Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857-863 4. 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*
Pe
rce
nt
(%)
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 even
if they are taking aspirin and/or after the addition
of aspirin in vitro
Barradas MA, Stansby G, Hamilton G, Mikhailidis DP. Diminished
platelet yield and enhanced platelet aggregability in platelet-rich
plasma 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 vascular
events and vascular death in patients with PAD.
For infrainguinal arterial surgery or balloon
angioplasty the benefit remains unproven, but
the number of trials to date is small
Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet
therapy for the prevention of myocardial infarction, stroke or vascular
death in patients with peripheral vascular disease. Br J Surg 2001;88:787-800
For patients with PAD, the number suffering
a 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
1.0 0.5 0.0 1.5 2.0
Control better Antiplatelet 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?
GUIDELINE LDL TARGETS
USA (2001) ≤ 2.6 mmol/l (100 mg/dl)
UK (2004) ≤ 2.0 mmol/l (80 mg/dl)
USA (2004) ≤ 1.8 mmol/l (70 mg/dl)
(optional) very high risk patients
UK JBS2 (2005) ≤ 2.0 mmol/l (80 mg/dl) (total
cholesterol 4.0 mmol/l; 160 mg/dl)
European (2007) ≤ 2.5 mmol/l (96 mg/dl)
Canada (2009) ≤ 2.0 mmol/l (80 mg/dl)
ESC/EAS (2011) ≤ 1.8 mmol/l (70 mg/dl)
AHA/ACC guidelines 2013
Focus on intensity of statin treatment – no LDL-C targets. Treat at 7.5% risk (? even at 5%). Aim for 50% fall in LDL-C levels for very high risk patients
NICE guidelines 2014
Prioritise at 10% risk. Use Q risk 2 engine. Aim for 40% fall in non-HDL-C levels.
Heart Protection Study
Patient Population:
20,536 patients
CHD (n=13,379)
Peripheral or
Cerebrovascular Disease (n=10,036)
Diabetes Mellitus (n=5,963)
Treated Hypertension
(n=8,455)
SIMVASTATIN 40 mg:
VASCULAR EVENT by PRIOR DISEASE
Risk ratio and 95% CI SIMVASTATIN PLACEBO Baseline feature (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 332 427
Diabetes 279 369
ALL PATIENTS 2042 2606 (19.9%) (25.4%)
24% SE 2.6 reduction (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% CI STATIN PLACEBO Stroke aetiology (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 5.3 reduction (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.
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 PAD
39 month follow-up study:
Statin No statin
n 318 342
Sudden IHD death 61 106
Fatal MI 51 84
New IHD events 153 251
WS Aronow Am J Cardiol 2002; 90: 789-91
PAD
SMOKING
• Most powerful predictor of PAD
• Major vascular risk factor
• Major risk factor for erectile
dysfunction
PAD
SMOKING • 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
PAD
HYPERTENSION
• Common in PAD
• ? accompanied by microalbuminuria
• PAD is the third risk factor for
stroke (after age and hypertension)
PAD
HYPERTENSION • 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
PAD
HYPERTENSION
Amlodipine + perindopril = less new PAD
compared with atenolol and bendroflumethiazide
(35%; p = 0.0001)
ASCOT-BPLA Lancet 2005; 366:895-906
PAD
DIABETES
• PAD is common among type 2 diabetic
patients - always check both ways!
• Hypertension and lipids are more
important than glycaemic control for
macrovascular complications
JS Berger, WR Hiatt
Medical Therapy in Peripheral Artery
Disease
Circulation 2012; 126: 491-500
0 1 2 3 4 5 6
INTERMITTENT CLAUDICATION*
*A post-hoc analysis of 4S
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
New or Worsening Intermittent Claudication
38%risk reduction
P=0.008
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
%o
fp
ati
en
ts
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
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
48%risk reduction
P=0.009
CAROTID BRUITS*
*A post-hoc analysis of 4S
Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.
2.5
2.0
1.5
1.0
0.5
0
%o
fp
ati
en
ts
Simvastatin
Placebo
Years
0 1 2 3 4 5 6
CAROTID BRUITS Meta-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 BRUITS
Yearly rates of cardiovascular death were also
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 the 4 trials in which direct comparisons of
patients with and without bruits were possible, the
OR for MI was 2.15 (1.67-2.78) and for cardiovascular
death 2.27 (1.49-3.49).
Pickett CA et al. Lancet 2008; 371: 1587-94
CAROTID BRUITS
Auscultation for carotid bruits in patients at
risk for heart disease could help select those
who might benefit the most from an aggressive
modification strategy for cardiovascular risk.
Paraskevas KI, et al. Neurol Res 2008;30:523-30
Pickett CA et al. Lancet 2008; 371: 1587-94
STROKE PREDICTORS
• Age
• BP
• Peripheral Arterial Disease
Evidence that lipids also predict stroke
LaRosa JC et al. N Engl J Med 2005; 352: 1425-35
Event Rates vs LDL Cholesterol during Statin Therapy in Secondary-Prevention Studies
ARBITER STUDY
CAROTID IMT:
• No reduction in 12 months with
pravastatin 40 mg
• Significant reduction after treatment with
atorvastatin 80 mg
ARBITER STUDY
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)
M Crisby et al. Circulation 2001; 103: 926-33
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
ABDOMINAL AORTIC ANEURYSMS
STATINS AND AAA EXPANSION
IN HUMANS
Second Manifestation of ARTerial disease
(SMART) study
Patients using lipid-lowering drugs had a 1.2
mm/y (95% CI -2.34 to -0.060) lower AAA
growth 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 inflammation
Kajimoto K et al. Atherosclerosis 2009; 206: 505-11
• Animal models
Atorvastatin 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: Weak
Quality 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!!
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!
