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 CHD EQUIVALENTS Diabetes Peripheral arterial disease Symptomatic carotid disease Abdominal aortic aneurysm

3 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)

4 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

5 CARDIOVASCULAR RISK FACTORS NON-MODIFIABLE Age Gender Family History Personal History Ethnicity MODIFIABLE Lipids Smoking BP Diabetes / IGT Obesity / Diet Coagulation factors Homocysteine

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

10 Survival (% of patients) Risk of death in PAD Normal subjects Asymptomatic PAD Symptomatic PAD Severe symptomatic PAD Year *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 Percent (%) ABI and risk of cardiovascular death 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 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)

23 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.

24 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)

25 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< )

26 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< )

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

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

29 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

30 STATINS AND PAD 39 month follow-up study: Statin No statin n Sudden IHD death Fatal MI New IHD events WS Aronow Am J Cardiol 2002; 90:

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

32 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:

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

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

35 HYPERTENSION Special advantages? Specific disadvantages? Systolic, diastolic or central BP? Target Organ Damage (TOD) Arterial stiffness; pulse wave velocity

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

37 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

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

39

40 % of patients INTERMITTENT CLAUDICATION* New or Worsening Intermittent Claudication *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

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

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

43 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

44 CAROTID ARTERY DISEASE

45 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:

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

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

48 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:

49 % of patients CAROTID BRUITS* Placebo 48% risk reduction P= Simvastatin Years *A post-hoc analysis of 4S Adapted from Pedersen TR et al Am J Cardiol 1998;81:

50 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 patient-years in those without bruits Pickett CA et al. Lancet 2008; 371:

51 CAROTID BRUITS Yearly rates of cardiovascular death were also higher in patients with bruits than in those without (2.85 [ ] per 100 patient-years vs 1.11 [ ] 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 ( ) and for cardiovascular death 2.27 ( ). Pickett CA et al. Lancet 2008; 371:

52 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: Pickett CA et al. Lancet 2008; 371:

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

54 Event Rates vs LDL Cholesterol during Statin Therapy in Secondary-Prevention Studies LaRosa JC et al. N Engl J Med 2005; 352:

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

56 ARBITER STUDY

57 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

58 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:

59 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

60 ABDOMINAL AORTIC ANEURYSMS

61 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:

62 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)

63 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

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

65 DIABETES Diabetes does not predict AAA!!

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

67 ATHEROSCLEROTIC RENAL ARTERY DISEASE (ARAS)

68 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

69 Renal Function and PAD ARAS Renal atherosclerosis Diabetes Cholesterol emboli

70 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

71 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

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