Paraskevi 10 Michailides

LIPIDS AND NON-CARDIAC VASCULAR DISEASE D P Mikhailidis BSc MSc MD FCPP FCP FRSPH FFPM FRCP FRCPath Academic Head

Dept. of Clinical Biochemistry (Vascular Disease Prevention Clinics) Royal Free campus University College London (UCL)

DECLARATION OF INTEREST • Attended conferences and gave talks sponsored

by Abbott, MSD and Genzyme

DECLARATION OF INTEREST • Lead: Guidelines for Medical Management of Carotid Artery Stenosis (Eur Soc Vasc Surg, ESVS) • Chairperson: European Expert Panel on Small Dense Low Density Lipoprotein • Co-chairperson: Expert Panel on Post-Prandial Hypertriglyceridaemia

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

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)

Common Types of Non-Cardiac Vascular Disease • Abdominal Aortic Aneurysms (AAA)

• Peripheral Arterial Disease (PAD) • Carotid Artery Disease • Atherosclerotic Renal Artery Disease (ARAS)

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)

LIPIDS AND ABDOMINAL AORTIC ANEURYSMS Do lipid levels predict the risk of AAA?

LIPIDS AND PREDICTING AAA • Cohort of 2035 men and 2310 women in Tromsø, Norway, who were 25 - 82 years old in 1994 • Risk factors for incident AAA over the next 7 years Forsdahl SH, et al. Circulation 2009;119:2202-8

LIPIDS AND PREDICTING AAA • • • • • • •

Age Male gender Smoking Hypertension Family history Hypercholesterolaemia Low HDL level

Forsdahl SH, et al. Circulation 2009;119:2202-8

LIPIDS AND PREDICTING AAA • Cohort study (n = 104,813) in northern California (Kaiser Permanente) • After a median of 13 years, 605 AAA events (490 in men and 115 in women; 91 [15%] fatal) were observed • Cholesterol was one predictor Iribarren C, et al. Ann Epidemiol 2007;17:669-78

LIPIDS AND PREDICTING AAA • DIABETES: A negative predictor of AAA? Why? • LINK WITH STATIN TREATMENT: Sometimes positive. Why?

STATINS AND OPERATIVE CARDIAC MORBIDITY AND MORTALITY • Decreased operative morbidity and 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 2013; 11: 112-20

STATINS AND OPERATIVE CARDIAC MORBIDITY AND MORTALITY IN AAA PATIENTS • • • • • •

Kertai MD et al. Eur J Vasc Endovasc Surg 2004;28:343-52 Kertai MD et al. Am J Med 2004;116:96-103 Leurs LJ, Vascular 2006;14:1-8 Schouten O et al.. J Vasc Surg 2006;44:435-41 Schouten O et al. Am J Cardiol 2005;96:861-6 Rigberg DA et al. J Vasc Surg 2006;43:224-9

STATINS AND AAA EXPANSION IN HUMANS

STATINS AND AAA EXPANSION IN HUMANS • •

130 AAA patients; 75 received statins Mean AAA size decreased from 4.6 ± 0.6 to 4.5 ± 0.6 cm in those on statins (p = NS) at 23 months, while it increased from 4.5 ± 0.6 to 5.3 ± 0.6 cm in those not on statins (p < 0.001) at 24 months Sukhija R, et al. Am J Cardiol 2006;97:279-80

STATINS AND AAA EXPANSION IN HUMANS â&#x20AC;˘ â&#x20AC;˘

150 patients with infrarenal AAA; 59 (39%) chronic statin users After a median follow-up of 3.1 years in multivariate linear regression analysis, statin users had a significant (p = 0.006) 1.16 mm (95% CI: 0.33-1.99 mm/year) lower annual AAA growth rate compared with non-users

Schouten O et al. Eur J Vasc Endovasc Surg 2006;32:21-6

STATINS AND AAA EXPANSION IN HUMANS • •

121 patients with an AAA >30 mm; 34 statin users After a mean follow-up of 3.6 ± 2.2 years, statinusers had a decreased (though not significant) linear AAA growth rate compared with non-users (1.9 ± 1.8 vs 2.6 ± 2.4 mm/year, respectively; p = 0.27)

Mosorini M, et al. Interact Cardiovasc Thorac Surg 2008;7:578-81

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

STATINS AND AAA EXPANSION IN HUMANS Negative studies • • • •

Karlsson L, et al. Eur J Vasc Endovasc Surg 2009;37:420-424 Ferguson CD, et al. Am Heart J 2010;159:307-13 Sweeting MJ, et al. J Vasc Surg 2010;52:1-4 Thompson A, et al. J Vasc Surg 2010;52:55-61

HOW COULD STATINS HELP PATIENTS WITH AAA? • Less inflammation Kajimoto K et al. Atherosclerosis 2009; 206: 505-11

• Animal models Atorvastatin decreased AAA diameter (MMP12, 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

CONCLUSIONS • Treatment targets for LDL-C • Elevated LDL-C and lower HDL-C levels predict AAA (weak effect)

• Statins and ↓ operative morbidity and mortality • Statins ↓ AAA expansion???

LIPIDS AND PERIPHERAL ARTERIAL DISEASE

WHY BOTHER WITH LIPIDS IN PAD? HIGH RISK PATIENTS (MI, CVA, ARAS)

• IMPROVING SYMPTOMS? • DECREASING RISK OF EVENTS?

PAD and the risk of vascular events, death and amputation Causes of death: • 55% coronary artery disease • 10% cerebrovascular disease • 25% non-vascular • < 10% other vascular

100

Patients (%)

80

60

Survival 40

Myocardial Infarction 20

Intervention Amputation

0 0

1

2

3

4

5

6

Time (years) Ouriel K. Lancet 2001; 358: 1257-64

7

8

9

10

Risk of death in PAD Survival (% of patients)

100

Normal subjects 75

Asymptomatic PAD†

50

Symptomatic PAD† Severe symptomatic PAD†

25

0 0

2

4

6

8

10

12

Year *Kaplan-Meier survival curves based on mortality from all causes. Large-vessel PAD Criqui MH et al. N Engl J Med 1992; 326: 381-86

PAD and high risk of MI and stroke

PAD

Increased risk of MI*

Increased risk of stroke*

4

2-3 

greater risk4 (includes only fatal MI and other CHD death)

greater risk3 (includes TIA)

5-7 

3- 4 

greater risk1 (includes death)

greater risk2 (includes TIA)

2-3 

9

greater risk2 (includes angina and sudden death†)

greater risk3

Post-MI

Poststroke 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

* †

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.

ABI and risk of cardiovascular death

Percent (%)

70 60 All-cause mortality

50

CVD mortality

40 30 20 10 0

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

*Mean participant follow-up 8.3 years

PAD • PLATELETS • LIPIDS • HYPERTENSION SMOKING • DIABETES

Heart Protection Study Patient Population: 20,536 patients

CHD

Peripheral (n=13,379) or Cerebrovascular Disease (n=10,036)

Diabetes Treated Mellitus Hypertension (n=5,963)

(n=8,455)

TATIN worse

SIMVASTATIN 40 mg: VASCULAR EVENT by PRIOR DISEASE Baseline feature

SIMVASTATIN (10269)

Previous MI

PLACEBO (10267)

1007

1255

452

597

CVD

182

215

PVD

332

427

Diabetes

279

369

Other CHD (not MI)

Risk ratio and 95% CI STATIN better STATIN worse

No prior CHD

ALL PATIENTS

2042 (19.9%)

2606 (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 Stroke aetiology Ischaemic

STATIN (10269)

PLACEBO (10267)

242

376

Haemorrhagic

45

53

Subarachnoid

12

10

Unknown

69

100

136

146

456 (4.4%)

613 (6.0%)

Unadjudicated ALL STROKE

0.4

Risk ratio and 95% CI STATIN better STATIN worse

0.6

0.8

1.0

1.2

27% SE 5.3 reduction (2P<0.00001) 1.4

Transient Ischaemic Attacks (TIA) â&#x20AC;˘ 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) â&#x20AC;˘ Carotid endarterectomy/angioplasty:

42 vs 82 (p= 0.0003)*

* included in non-coronary revasc.

INTERMITTENT CLAUDICATION*

% of patients

New or Worsening Intermittent Claudication 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Placebo

38% risk reduction P=0.008

Simvastatin

0

*A post-hoc analysis of 4S

1

2

3 Years

Adapted from Pedersen TR et al Am J Cardiol 1998;81:333-335.

4

5

6

MM McDermott et al.

Circulation 2003;107:757 â&#x20AC;˘ Superior leg functioning after statin â&#x20AC;˘ Independent of cholesterol lowering

STATINS AND PAD 39 month follow-up study: Statin n 318 Sudden IHD death 61 Fatal MI 51 New IHD events 153

No statin 342 106 84 251

WS Aronow Am J Cardiol 2002; 90: 789-91

PAD and INFLAMMATION • Raised CRP in PAD • CRP predicts events in healthy subjects or patients with vascular disease. Even if lipids are normal

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

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

LIPIDS AND CAROTID ARTERY DISEASE

STROKE PREDICTORS • Age • BP • Peripheral Arterial Disease

Evidence that lipids also predict stroke

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: 549-559

Kaplan-Meier Curves for Stroke and TIA

SPARCL. N Engl J Med 2006;355:549-559

Kaplan-Meier Curves for Coronary and Cardiovascular Events

SPARCL. N Engl J Med 2006;355:549-559

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

Omega-3 fish oils and carotid plaque Some studies show improved Intima Media Thickness (IMT) as well as carotid compliance.

Mita T, et al. Atherosclerosis 2007; 191: 162-7

Omega-3 fish oils and carotid plaque Atherosclerotic plaques readily incorporate n-3 PUFAs from fish-oil supplementation, inducing changes that can enhance stability of atherosclerotic plaques. This could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake.

Thies F et al. Lancet 2003; 361: 477 - 85

CAROTID BRUITS*

2.5

48%

% of patients

2.0 Placebo

risk reduction P=0.009

1.5 1.0 Simvastatin

0.5 0

0

1

2

3 Years

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

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 patientyears in those without bruits Pickett CA et al. Lancet 2008; 371: 1587-94

CAROTID BRUITS Rates of cardiovascular death 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 with direct comparisons of patients with and without bruits, 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 could help select those who might benefit most from aggressive treatment of vascular risk.

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

ARBITER STUDY CAROTID IMT: • No reduction in 12 months with pravastatin 40 mg • Significant reduction after treatment with atorvastatin 80 mg

ARBITER STUDY

Liapis CD, Bell PF, Mikhailidis DP, et al; 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, et al; ESVS Guidelines Collaborators; European Society for Vascular Surgery. ESVS Guidelines: Section B -- Diagnosis and investigation of patients with carotid artery stenosis. Curr Vasc Pharmacol 2010; 8: 682 91

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 MMP-2 immunoreactivity (p < 0.05) Greater tissue inhibitor of MMP-1 (TIMP-1) immunoreactivity (p < 0.05) • Higher collagen content (p < 0.005) M Crisby et al. Circulation 2001; 103: 926-33

LIPIDS AND 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

Change in serum creatinine (%) in the structured and the usual care groups Usual Care no hypolipidemics n=687 Structured Care no atorvastatin n=17

Usual Care hypolipidemics n=113 Structured Care atorvastatin n=783

5

3% 2%

0

-4%

-5

-10

-9.6% -15 0

6w

6m

12 m

18 m

24 m

30 m

Athyros VG et al. J Clin Pathol 2004;57:728-34

36 m

42 m

48 m

A professor is someone who talks in someone elseâ&#x20AC;&#x2122;s sleep WH Auden 1907 â&#x20AC;&#x201C; 1973 English poet I hope that I kept you awake!