NON-CORONARY ARTERIAL DISEASE

Transcription

1 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

2 DECLARATION OF INTEREST Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec

3 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),

4 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

5 CHD EQUIVALENTS Diabetes Peripheral arterial disease Symptomatic carotid disease Abdominal aortic aneurysm Chronic kidney disease (egfr <60 ml/min/1.73m 2 Rheumatoid arthritis (?psoriasis + arthritis, SLE)

6 Common Types of Non-Cardiac Vascular Disease Abdominal Aortic Aneurysms (AAA) Peripheral Arterial Disease (PAD) Carotid Artery Disease Atherosclerotic Renal Artery Disease (ARAS)

7 NON-CARDIAC VASCULAR DISEASE PLATELETS LIPIDS HYPERTENSION SMOKING DIABETES

8 PERIPHERAL ARTERIAL DISEASE

9 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 Patients (%) Time (years) Survival Myocardial Infarction Intervention Amputation Ouriel K. Lancet 2001; 358:

10 Risk of death in PAD Survival (% of patients) Year Normal subjects Asymptomatic PAD Symptomatic PAD Severe symptomatic PAD *Kaplan-Meier survival curves based on mortality from all causes. Large-vessel PAD Criqui MH et al. N Engl J Med 1992; 326:

11 PAD and high risk of MI and stroke PAD Increased risk of MI* 4 greater risk 4 (includes only fatal MI and other CHD death) Increased risk of stroke* 2-3 greater risk 3 (includes TIA) Post-MI Poststroke 5-7 greater risk 1 (includes death) 2-3 greater risk 2 (includes angina and sudden death ) 3-4 greater risk 2 (includes TIA) 9 greater risk 3 1. Adult Treatment Panel II. Circulation 1994; 89: Kannel WB. J Cardiovasc Risk 1994; 1: Wilterdink JI, Easton JD. Arch Neurol 1992; 49: Criqui MH et al. N Engl J Med 1992; 326: * 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.

12 ABI and risk of cardiovascular death 70 Percent (%) All-cause mortality CVD mortality Resnick HE et al. Circulation 2004; 109: Baseline ABPI* *Mean participant follow-up 8.3 years

13 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

14 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:

15 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 = ; p = 0.02

16 Effect of Antiplatelet Therapy on Vascular events* in PAD % odds reduction Intermittent claudication Peripheral grafting Peripheral angioplasty All trials in PAD 23% ± 8 All trials 22% ± Antiplatelet better *Vascular events = MI, stroke or vascular death Antithrombotic Trialists Collaboration. BMJ 2002; 324: Control better

17 PAD results in CAPRIE PAD subgroup: Clopidogrel, n = 3,223; Aspirin, n = 3,229 Relative Risk Reduction = 23.8% ( ), p = over 1.9 years

18 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

19 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).

20 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: ,

21 WHY BOTHER WITH LIPIDS IN PAD? HIGH RISK PATIENTS (MI,CVA,ARAS) Improving symptoms Decreasing the risk of events Preventing PAD?

22 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)

23 ATIN worse SIMVASTATIN 40 mg: VASCULAR EVENT by PRIOR DISEASE Baseline SIMVASTATIN PLACEBO Risk ratio and 95% CI feature (10269) (10267) STATIN better STATIN worse Previous MI Other CHD (not MI) No prior CHD CVD PVD Diabetes ALL PATIENTS (19.9%) (25.4%) %SE 2.6 reduction (2P< )

24 SIMVASTATIN 40 mg: STROKE by AETIOLOGY Stroke STATIN PLACEBO Risk ratio and 95% CI aetiology (10269) (10267) STATIN better STATIN worse Ischaemic Haemorrhagic Subarachnoid Unknown Unadjudicated ALL STROKE (4.4%) (6.0%) 27% SE 5.3 reduction (2P< )

25 Transient Ischaemic Attacks (TIA) 204 vs 250 (p = 0.02) TIAs are ischaemic events that predict an increased risk of stroke.

26 Non-Coronary revascularization 450 vs 532 (p= 0.006) Carotid endarterectomy/angioplasty: 42 vs 82 (p= )* * included in non-coronary revasc.

27 LIMB SALVAGE Patients were selected from 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 < ), 90 days (15.5 vs 19.3%; p < ) and 1 year (20.9 vs 25.6%; p < ). 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:

28 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 MACCE and 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:

29 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, ; p = ]. The composite of cardiovascular death/myocardial infarction/stroke was similarly reduced (HR, 0.83; 95% CI, ; 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:

30 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 (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:

31 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:

32 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 ) and incidence of stroke (OR 0.77, 95% CI ). A trend towards improved CV mortality (OR 0.62, 95% CI ), MI (OR 0.62, 95% CI ) and the composite of death/mi/stroke (OR 0.91, 95% CI ) was identified. Meta-analyses of studies performing adjustments showed decreased allcause mortality in statin users (HR 0.77, 95% CI ). Antoniou GA, et al. Statin therapy in lower limb peripheral arterial disease: Systematic review and meta-analysis. Vascul Pharmacol 2014; 63: 79-87

33 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 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 ; 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 ; 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:

34 PAD SMOKING Most powerful predictor of PAD Major vascular risk factor Major risk factor for erectile dysfunction

35 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:

36 Smoking and Biochemical and Haematological Variables HDL TG Insulin resistance Bilirubin Fibrinogen White Cell Count

37 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:

38 PAD HYPERTENSION Common in PAD? accompanied by microalbuminuria PAD is the third risk factor for stroke (after age and hypertension)

39 PAD HYPERTENSION Aggressive treatment > 1 drug often needed adherence (compliance) 24h control is essential Benefit in PAD (e.g. HOPE trial)

40 HYPERTENSION Special advantages? Specific disadvantages? Systolic, diastolic or central BP? Target Organ Damage (TOD) Arterial stiffness; pulse wave velocity 24 h ABPM (dipping, spiking)

41 PAD HYPERTENSION Amlodipine + perindopril = less new PAD compared with atenolol and bendroflumethiazide (35%; p = ) ASCOT-BPLA Lancet 2005; 366:

42 PAD DIABETES 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

43 Risk Factors for PAD: Diabetes NHANES (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 = ) 1. Lane JS, et al. J Vasc Surg 2006; 44: Murabito JM, et al. Circulation 1997; 96: 44-9

44 Risk Reduction: Diabetes (DM) Aggressive treatment of glycaemia in DM Not definitively shown to decrease CVD risk of patients with DM and PAD 1 DCCT (type 1 DM): reduced risk for lower-extremity macrovascular events by 22%; not significant 2 UKPDS (type 2 DM): reduced MI risk by 16%; not significant 3 Meticulous foot care essential to reduce risk for ulceration, gangrene and amputation 1 DCCT = Diabetes Control and Complications Trial; UKPDS = United Kingdom Prospective Diabetes Study; ADA = American Diabetes Association 1. Hirsch AT, et al. Circulation 2006; 113: e DCCT Investigators. Am J Cardiol 1995; 75: UKPDS Group. Lancet 1998; 352:

45 ASSESSING PAD IN DIABETES Audible Doppler waveform Ankle-brachial pressures (ABI) Toe:brachial index (TBI) Transcutaneous pressure of oxygen (TcPO 2 ) Pulse reappearance time (PRT) Pulse oximetry (measures O 2 saturation of blood) NB why not angiography?

46 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]

47 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 HbA 1c 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.

48 DM and PAD 3406 patients (mean age: 71.7 ± 11.8 years, 61% male). Significant association of age (OR 1.67, 95%CI , p < 0.001), male gender (OR 1.23, 95%CI , p = 0.016), DM (OR 1.99, 95%CI , p < 0.001) and renal insufficiency (OR 1.62, 95%CI , 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:

49 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

50 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: MetS and PAD in the National Health and Nutrition Examination Survey ( ): 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 ( ). J Clin Hypertens (Greenwich) 2012; 14: 144-8

51 Obesity and PAD Not a straightforward relationship. May be influencd by several factors (e.g. smoking status, quality of life, comorbidities 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: Kato J. Obesity paradox in peripheral vascular disease. Atherosclerosis 2013; 229:

52 Obesity and PAD Overlap with: Obstructive Apnoea Syndrome (OSA) Non-Alcoholic Fatty Liver Disease (NAFLD) Epicardial fat Release of adipokines from visceral fat

53 JS Berger, WR Hiatt Medical Therapy in Peripheral Artery Disease Circulation 2012; 126:

54

55 INTERMITTENT CLAUDICATION* New or Worsening Intermittent Claudication % of patients *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81: Years Placebo Simvastatin 38% risk reduction P=0.008

56 MM McDermott et al. Circulation 2003;107:757 Superior leg functioning after statin Independent of cholesterol lowering

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

58 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

59 CAROTID ARTERY DISEASE

60 Statin pre-treatment Among TIA + carotid patients, nonprocedural 7-day stroke risk was 3.8% (CI, %) with statin treatment at TIA onset, compared with 13.2% (CI, %) 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, ) but not non-stenosis patients (OR, 1.3; CI, ; p for interaction, 0.008). On multivariable logistic regression, the association remained. Merwick Á, et al. Stroke 2013; 44:

61 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:

62 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: Paraskevas KI, Veith FJ, Liapis CD, Mikhailidis DP. Curr Vasc Pharmacol 2013;11:112-20

63 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: 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

64 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

65 LIPIDS, CAROTID ENDARTERECTOMY AND ANATOMICAL DURABILITY LIPID LOWERING DRUGS, protective for: Early restenosis: OR = (p< 0.007) Early and late anatomical failure: OR = (p< 0.03) and (p< ) Progression of disease: OR = (p< ) LaMuraglia GM et al. J Vasc Surg 2005; 41: 762-8

66 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:

67 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 = , p = 0.007) was observed The reduction in hscrp correlated inversely with the increase in GSM (r = , p = 0.021) Marchione P et al. J Stroke Cerebrovasc Dis 2015;24:138-43

68 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

69 INTENSIVE LDL-C LOWERING The combination of atorvastatin + ezetimibe can further decrease LDL-C and hscrp levels and have effects on the progression of carotid atherosclerosis in elderly patients with hypercholesterolemia compared with atorvastatin monotherapy Luo P, et al. Genet Mol Res 2014;13: Comment in Genet Mol Res 2014;13:4805-7

70 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

71 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

72 PLATELETS Asymptomatic Carotid Emboli Study (ACES) prospective study 477 patients with asymptomatic carotid stenosis followed-up for 2 years Antiplatelet agents (p < ) and antihypertensives (p < ) were independent predictors of lower risk of any stroke or cardiovascular death. King A et al. Stroke 2013;44:542-6

73 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: 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: 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

74 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 ) 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: S (15) [Epub ahead of print]

75 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:

76 Kaplan-Meier Curves for Stroke and TIA SPARCL. N Engl J Med 2006;355:549-59

77 Kaplan-Meier Curves for Coronary and Cardiovascular Events SPARCL. N Engl J Med 2006;355:549-59

78 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:

79 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

80 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

81 PLATELETS Asymptomatic Carotid Emboli Study (ACES) prospective study 477 patients with asymptomatic carotid stenosis followed-up for 2 years Antiplatelet agents (p < ) and antihypertensives (p < ) were independent predictors of lower risk of any stroke or cardiovascular death. King A et al. Stroke 2013;44:542-6

82 CAROTID BRUITS* 2.5 % of patients Placebo Simvastatin 48% risk reduction P= Years *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81:

83 CAROTID BRUITS Meta-analysis of 17,295 patients with patient-years of follow-up. MI in patients with carotid bruits was 3.69 (95% CI ) per 100 patient-years compared with 1.86 ( ) per 100 patientyears in those without bruits Pickett CA et al. Lancet 2008; 371:

84 CAROTID BRUITS Yearly rates of cardiovascular (CV) death were higher in patients with bruits than in those without (2.85 [ ] per 100 patient-years vs 1.11 [ ] per 100 patient-years). In 4 trials comparing patients with and without bruits, the OR for MI was 2.15 ( ) and for CV death 2.27 ( ). Pickett CA et al. Lancet 2008; 371:

85 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 CV risk. Paraskevas KI, et al. Neurol Res 2008;30: Pickett CA et al. Lancet 2008; 371:

86 STROKE PREDICTORS Age BP Peripheral Arterial Disease Evidence that lipids also predict stroke

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

88 ARBITER STUDY

89 ABDOMINAL AORTIC ANEURYSMS

90 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 to ) 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:

91 HOW COULD STATINS HELP PATIENTS WITH AAA? Less inflammation Kajimoto K et al. Atherosclerosis 2009; 206: Animal models Atorvastatin decreased AAA diameter (MMP- 12, ICAM) independently of lipid levels. Early action (1 week)

92 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

93 SMOKING Most powerful predictor of PAD and AAA Major vascular risk factor

94 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!!

95 PLATELETS Which agent? What to do when you use antiplatelet agents and the patient will undergo surgery (including EVAR)? DES coronary stent problem

96 ATHEROSCLEROTIC RENAL ARTERY DISEASE (ARAS)

97 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

98 Renal Function and PAD ARAS Renal atherosclerosis Diabetes Cholesterol emboli

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

100 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

101 A professor is someone who talks in someone else s sleep WH Auden English poet I hope that I kept you awake!