NON-CORONARY ARTERIAL DISEASE

Transcription

1 NON-CORONARY ARTERIAL DISEASE D P Mikhailidis BSc MSc MD FCPP FCP FFPM FRCP FRCPath 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, Libytec and Astra Zeneca

3 DECLARATION OF INTEREST Editor-in-Chief of: Curr Med Res Opin Expert Opin Pharmacother Angiology Curr Vasc Pharmacol Open Cardiovasc Med J Expert Rev Cardiovasc Ther Clinical Lipidology Journal of Drug Assessment

4 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),

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

14 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)

15 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< )

16 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< )

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

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

19 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

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

21 LIMB SALVAGE Patients were selected from Medicare claims with claudication (n = 8128), rest pain (n = 3056), ulceration/gangrene (n = 11,770), 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. Circ Cardiovasc Interv 2013; 6:

22 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 (3.4. mmol/l) had increased HRs of MACCE and mortality vs those with lower LDL-C levels. Westin GG, et al. J Am Coll Cardiol 2014; 63:

23 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 CV death/mi/stroke was similarly reduced (HR, 0.83; 95% CI, ; p = 0.01). Kumbhani DJ, et al.; REACH Registry Investigators. Eur Heart J 2014; 35:

24 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 Of these, 1537 (74%) were on statins perioperatively and at 1 year followup 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:

25 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). Subgroup analysis: survival advantage was evident in patients on statins with CLI (5 year survival, 63 vs 54%; log-rank, p =.01) but not claudication (5 year survival, 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. J Vasc Surg 2015; 61:

26 LIMB SALVAGE AND EVENTS 12 observational cohort studies and 2 randomised trials: 19,368 PAD patients. Meta-analysis. 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

27 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:

28 STATINS, PAD AND EVENTS O'Donnell TFX, et al. J Vasc Surg 2017; 66: Use of the recommended intensity of statin therapy in compliance with 2013 American College of Cardiology/American Heart Association lipid management guidelines is associated with significantly improved survival and lower major adverse limb (1019 limbs from 931 patients with a median follow-up of 380 days) event (MALE) rate in patients undergoing revascularization for chronic limb-threatening ischemia. In multivariable analysis, discharge on any statin was associated with lower mortality (hazard ratio [HR], 0.71; 95% CI, ; p < 0.01). Patients >75 years old and 75 years old accrued similar benefit.

29 Above-knee amputations (AKAs) and below-knee amputations (BKAs) are associated with high postoperative mortality rates. 811 patients underwent AKA (n = 325) or BKA (n = 486). In the year after amputation, medium-intensity statin (HR, 0.64; 95% CI, ) and high-intensity statin (HR, 0.56; 95% CI, ) conferred a mortality benefit. Lowintensity statins did not confer protection from mortality. At 1 year after amputation, only 44.7% of patients were receiving appropriate statin therapy. DeCarlo C, et al. J Vasc Surg 2017; 66:

30 Nationwide Taiwan DM database in from ,332 patients aged 20 years with DM and PAD. Only statin users were associated with the risk reduction of lower-extremities amputation (HR, 0.77; 95% CI, ) and CV death (HR, 0.78; 95% CI, ) when taking competing risk of death into consideration. Hsu CY, et al. J Clin Endocrinol Metab 2017; 102:

31 Patients (n=3,642) had PAD (1,505 with no prior MI or stroke) in the FOURIER trial. Evolocumab significantly reduced the primary end point in patients with PAD (HR 0.79; 95% CI, ; p = ) and without PAD (HR 0.86; 95%CI, ; p = ; Pinteraction = 0.40). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, ; p = ) with consistent effects in those with and without known PAD. Bonaca MP, et al. Circulation 2018; 137:

32 CAROTID ARTERY DISEASE

33 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]

34 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:

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

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

37 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:

38 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

39 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

40 Statin pre-treatment 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). Multivariable logistic regression: the association remained. Merwick A, et al. Stroke 2013; 44:

41 Statin pre-treatment 156 patients randomized to 600 mg (n = 78) or 300 mg (n = 78) clopidogrel load 6 h before 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:

42 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

43 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

44 Carotid Stenting and Statins Consecutive series of 397 symptomatic carotid artery stenosis ( 50% stenosis on angiography) treated with stenting. Statin pretreatment divided into 3 categories according to atorvastatin dose: none (n = 158; 39.8%), standard dose (<40 mg, n = 155; 39.0%) and high dose ( 40 mg; n = 84; 21.2%). Peri-procedural complication rates across the 3 categories of statin use were 12.0, 4.5 and 1.2%. After adjustment, p for trend = Hong JH, et al. Stroke 2017; 48:

45 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

46 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:

47 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 = -.456, p =.007) was observed The reduction in hscrp correlated inversely with the increase in GSM (r = -.398, p =.021) Marchione P et al. J Stroke Cerebrovasc Dis 2015;24:138-43

48 Study suggests statin therapy is associated with significant reductions in in lipid-rich-necrotic-core (LRNC) volumes at 1-year of statin therapy on serial carotid MRI. However, no significant reduction in carotid wall volume was seen. Brinjikji W, et al. J Neuroradiol 2017; 44:

49 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

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

51 ARBITER STUDY

52 Bos S, Duvekot MH, Ten Kate GR, Verhoeven AJ, Mulder MT, Schinkel AF, Nieman K, Watts GF, Sijbrands EJ, Roeters van Lennep JE. Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study. Atherosclerosis 2017; 256: 62-6 Braamskamp MJAM, Langslet G, McCrindle BW, Cassiman D, Francis GA, Gagne C, Gaudet D, Morrison KM, Wiegman A, Turner T, Miller E, Kusters DM, Raichlen JS, Martin PD, Stein EA, Kastelein JJP, Hutten BA. Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label). Circulation 2017; 136: Statin treatment in patients with FH reversed some carotid changes

53 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

54 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:

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

56 Good reviews Naylor AR. Medical treatment strategies to reduce perioperative morbidity and mortality after carotid surgery. Semin Vasc Surg 2017; 30: Cheng SF, Brown MM. Contemporary medical therapies of atherosclerotic carotid artery disease. Semin Vasc Surg 2017; 30: 8-16

57 ABDOMINAL AORTIC ANEURYSMS

58 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:

59 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)

60 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

61 The main determinants of survival following AAA repair are preexisting risk factors. Meta-analysis: 24 studies (53,118 patients) published between1989 and 2015, were included. Statins improved survival following ( 1 year) open repair with a hazard ratio and 95% CI of 0.75 ( ). Khashram M, et al. Ann Vasc Surg 2017; 39:

62 Single centre, retrospective cohort study; 640 patients with AAA treated by open surgery. Stratified analysis using the Mantel-Haenszel method on quintiles of the propensity score: adjusted odds ratio = 0.43 (95% CI: ); 57% reduction of 30-day mortality for statin users. The adjusted rate ratio was 0.62 (95% CI: ); a reduction of long-term mortality of 38% for statin users compared with non-users for a median follow-up of 3.93 years. Mathisen SR, Abdelnoor M. Vasc Med 2017; 22:

63 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!!

64 ATHEROSCLEROTIC RENAL ARTERY DISEASE (ARAS)

65 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

66 Renal Function and PAD ARAS Renal atherosclerosis Diabetes Cholesterol emboli

67 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

68 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

69 Are statins useful in the elderly? The answer is a definite maybe? But why are we uncertain? Toth PP. Treatment of Dyslipidemia in Elderly Patients With Coronary Heart Disease: There Are Miles to Go Before We Sleep. J Am Coll Cardiol ; 66:

70 Are statins useful in the elderly? The elderly die of many causes (high comorbidity) so we need to separate causes of death Those who have subclinical problems may also have a low cholesterol Vascular lesions may be too advanced to respond to statins Heart failure is very common in the elderly and may not respond effectively to statins There are very few statin trials specifically focussed on the elderly Is treatment to target or are prescribers using lower doses in the elderly? Statin-associated new onset diabetes (NOD) may be more common and play a bigger role in the elderly. Some loss of efficiency? Adherence to treatment may be lower in the elderly (e.g. cognitive ability, cost and polypharmacy) Some evidence comes from heterogeneous populations (e.g. primary or secondary prevention). Menopause = increased risk Who are the elderly? > 65, >70 or >75 years old? [PROSPER years]

71 STROKE PREDICTORS Age (90% of strokes above the age of 65 years) BP Peripheral Arterial Disease Evidence that lipids also predict stroke

72 PROSPER Pravastatin 40 mg vs placebo: weak and rarely used statin Age years: common definition for elderly is >65 years Baseline cholesterol from 4.0 to 9.0 mmol/l: heterogeneity Follow-up = 3.2 years: short Mixed population (n = 5804; vascular disease +/-): heterogeneity Shepherd J, et al. Lancet 2002; 360:

73 PROSPER CHD death or non-fatal MI or fatal or nonfatal stroke HR 0.85 (p = 0.014): small effect Fatal or non-fatal stroke: 131 vs 135: NS and more with pravastatin! Non vascular deaths greater by about 1% than vascular deaths. Common problem with elderly populations Cancer 58 vs 65, p = 0.02: significantly more with pravastatin! Shepherd J, et al. Lancet 2002; 360:

74 OTHER TRIALS Mostly not randomised surveys, or subgroup/post hoc analyses of trials (e.g. CARDS, JUPITER, HPS, AFCAPS/TexCAPS, ASCOT-LLA, 4S). Pedro-Botet J et al. Statins for primary cardiovascular prevention in the elderly. J Geriatr Cardiol 2015; 12: 431-8

75 2016 Joint European Society of Cardiology Guidelines No differences in the relative reduction between men and women and between younger and older age or between those with and without DM. Piepoli MF et al. Euro Heart J doi: /eurheartj/ehw106 No differences in the relative reduction between younger and older age (n = 134,537) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2012; 380:

76 Aged 80 and older (mean 85.2) hospitalized from Jan 2006 to Dec 2010 with AMI, unstable angina pectoris, or chronic CAD and discharged alive (n = 1,262); n = 913 received and 349 did not receive a discharge prescription for a statin. Median follow-up: 3.1 years. After adjusting for baseline differences between groups and propensity for receiving statin therapy, the effect of statins on mortality was not significant (HR = 0.88, 95%CI = ). Confounders: more effective vascular prevention treatment in statin group. Adherence? Co morbidity? Overall mortality. Rothschild DP, et al. J Am Geriatr Soc 2016 Jun 13. doi: /jgs.14207

77 years from the general population Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association found In two cohorts, CV mortality was highest in the lowest LDL- C quartile and with statistical significance; in 7 cohorts, no association was found Heterogeneous studies Association is not proof of causation Ravnskov U, et al. BMJ Open 2016;6:e010401

78 Randomized trials comparing statins vs placebo in subjects (age 65 years) without established CVD 8 trials enrolling 24,674 subjects (mean age: 73.0 ± 2.9 years; mean follow up 3.5 ± 1.5 years) Significantly reduced risk of MI by 39.4% (RR: 0.61 [95% CI: 0.43 to 0.85]; p = 0.003) and risk of stroke by 23.8% (RR: 0.76 [95% CI: 0.63 to 0.93]; p = 0.006). In contrast, the risk of all-cause death (RR: 0.94 [95% CI: 0.86 to 1.03]; p = 0.21) and of CV death (RR: 0.91 [95% CI: 0.69 to 1.20]; p = 0.493) were not significantly reduced. New cancer onset did not differ between statin- and placebo-treated subjects (RR: 0.99 [95% CI: 0.85 to 1.15]; p = 0.89) Savarese G, et al. J Am Coll Cardiol 2013; 62:

79 Ble A, et al. J Gerontol A Biol Sci Med Sci 2016 May 4. pii: glw082. [Epub ahead of print] Primary care electronic medical records from the UK Clinical Practice Research Datalink. Compared older (60+) statin users and 1:1 propensity-score-matched controls (total n = 12,156; 38% > 80 years old). Follow-up: 10 years Mean age 76.5 ± 9.2 years. Statins associated with near significant reduction in MI recurrence (subhazard ratio = 0.84, , p =.073), with protective effect in the age group (0.73, ) but a nonsignificant result in the 80+ group (1.06, ; age interaction p =.094). No significant associations were found for stroke or dementia. Data suggest an increased risk of falls (1.36, ) and fractures (1.33, ) in the first 2 years of treatment, particularly in the 80+ group.

80 Treatment was associated with lower all-cause mortality. (HR = 0.62, , p <.001). Increasing age (60-79: 0.62, , p <.001; 80+: 0.77, , p <.001; p for interaction =.010), but not burden of disease, affected the association between statins and all-cause mortality Statin use was associated with health care cost savings in the group but higher costs in the 80+ group Ble A, et al. J Gerontol A Biol Sci Med Sci 2016 May 4. pii: glw082. [Epub ahead of print]

81 5152 men and women from the Age, Gene/Environment Susceptibility-Reykjavik Study. Mean age 77 years (range: years) Prevalence of type 2 DM was 12.4% of which 35% used statins. Statin use was associated with a 50% (95% CI 8 to 72%) lower CV mortality and 53% (29 to 68%) lower allcause mortality in persons with DM. For those without DM, statin use was associated with a 16% (-24 to 43%) lower CV and 30% (11 to 46%) lower all-cause mortality Persons with DM on statins had a comparable risk of CV and all-cause mortality asthe general population without DM The effect was independent of glycaemic control Olafsdottir E, et al.. BMJ Open 2011;1(1):e000132

82 Inclusion criteria: randomized allocation to statin or placebo, documented CHD, 50 elderly patients (defined as age 65 years) and 6 months of follow-up 9 trials, 19,569 patients (age range: 65-82). Pooled rates of all-cause mortality were 15.6% with statins and 18.7% with placebo. RR 0.78; 95% credible interval [CI] over 5 years. Furthermore, statins reduced CHD mortality by 30% (RR 0.70; 95% CI ), nonfatal MI by 26% (RR 0.74; 95% CI ), need for revascularization by 30% (RR 0.70; 95% CI ), and stroke by 25% (RR 0.75; 95% CI ) Afilalo J, et al. J Am Coll Cardiol 2008; 51: 37-45

83 Randomized controlled trials comparing any statins with placebo or usual care for primary prevention of CVD in subjects aged 65 years Eight studies (n = 25,952) were included in the meta-analysis Statins significantly reduced the risks of composite major adverse CV events (RR 0.82, 95% CI ), nonfatal MI (0.75, ) and total MI (0.74, ) Treatment effects of statins were insignificant in fatal MI (0.43, ), stroke (fatal: 0.76, ; nonfatal: 0.76, ; total: 0.85, ) and all-cause mortality (0.96, ) Teng M, et al. Drugs Aging 2015; 32:

84 Significant differences were not observed in myalgia (0.88, ), elevation of hepatic transaminases (0.98, ), new-onset diabetes (1.07, ), serious adverse events (1.00, ) and discontinuation due to adverse events (1.10, ). Myopathy, rhabdomyolysis and cognitive impairment was largely unreported in the included trials. Teng M, et al. Drugs Aging 2015; 32:

85 CONCLUSIONS Adherence to statins in the elderly Depriving treatment in the face of guidelines? Common sense (e.g. terminal cases or potential problem with first do no harm ) Clearly more evidence required

86 How to address discontinuation Pharmacists, nurses, auto-reminders, refill reminders Knowledge of guidelines. Confusion too many guidelines Side effects real or imagined; Prescriber s role: take your time Patient participation; know your level and why you need to achieve it Alternative medication optins (e.g. ezetimibe, PCSK9 inhibitors); drug spacing Dealing with risk factors for side effects: thyroid, vit D? CoQ10? Monitor: new ACC guidelines; wireless-enabled pill bottles or even pills Polypharmacy; polypill; Special cases: discontinuation on admission for ACS Cost to patient or prescriber s budget Patient characteristics: other drugs, age, exercise, genetics, dementia, motivation, effect of the press on patients Defining statin intolerance

87 Stroes ES, et al.; European Atherosclerosis Society Consensus Panel. Statinassociated muscle symptoms: impact on statin therapy-european Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36: Banach M, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci 2015; 11: 1-23 Statin-associated muscle symptoms = SAMS The second panel statement considers SAMS as well as other side effects associated with statin use (e.g. liver)

88 OTHER SPECIFIC GROUPS GENDER: As shown in the ESC 2016 guideline slide there is no difference between men and women in terms of benefit from statin treatment. However, - Pre-menopausal vs post-menopausal - HRT - Representation in trials

89 OTHER SPECIFIC GROUPS HIV: Complex situation: Drug interactions Other factors: inflammation, lipodystrophy, insulin resistance and new onset diabetes

90 OTHER SPECIFIC GROUPS CKD: Kidney dysfunction = CHD equivalent

91 Change in serum creatinine (%) in the structured and the usual care groups 5 Usual Care no hypolipidemics n=687 Usual Care hypolipidemics n=113 Structured Care no atorvastatin n=17 Structured Care atorvastatin n=783 3% 2% % % w 6 m 12 m 18 m 24 m 30 m 36 m 42 m 48 m Athyros VG et al. J Clin Pathol 2004; 57:

92 OTHER TRIALS CARDS: Diabetes type 2; atorvastatin 10 mg vs placebo HPS: high risk patients; simvastatin 40 mg vs placebo TNT: stable CHD; atorvastatin 10 mg vs atorvastatin 80 mg

93

94 SHARP: Assessment of LDL-lowering

95 SHARP: Major Atherosclerotic Events by renal status at randomization Eze/simv (n=4650) Placebo (n=4620) Risk ratio (95% CI) Non-dialysis (n = 6247) 296 (9.5%) 373 (11.9%) Dialysis (n = 3023) 230 (15.0%) 246 (16.5%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) No significant heterogeneity between nondialysis and dialysis patients (p = 0.25) Eze/simv better Placebo better

96 SHARP: Cause-specific mortality Event Eze/simv (n = 4650) Placebo (n = 4620) Risk ratio & 95% CI Coronary 91 (2.0%) 90 (1.9%) Other cardiac 162 (3.5%) 182 (3.9%) Subtotal: Any cardiac 253 (5.4%) 272 (5.9%) 7.4% SE 8.4 Eze/simv better Placebo better reduction (p=0.38) Stroke 68 (1.5%) 78 (1.7%) Other vascular 40 (0.9%) 38 (0.8%) Subtotal: Any vascular 361 (7.8%) 388 (8.4%) 7.3% SE 7.0 reduction Cancer 150 (3.2%) 128 (2.8%) (p=0.30) Renal 164 (3.5%) 173 (3.7%) Other non-vascular 354 (7.6%) 311 (6.7%) Subtotal: Any non-vascular 668 (14.4%) 612 (13.2%) Unknown cause 113 (2.4%) 115 (2.5%) Total: Any death 1142 (24.6%) 1115 (24.1%) 8.6% SE 5.8 increase (p=0.14) 1.9% SE 4.2 increase (p=0.65)

97 SHARP: Renal outcomes Event Eze/simv (n = 3117) Placebo (n = 3130) Risk ratio & 95% CI Main renal outcome End-stage renal disease (ESRD) 1057 (33.9%) 1084 (34.6%) 0.97 ( ) Tertiary renal outcomes ESRD or death 1477 (47.4%) 1513 (48.3%) 0.97 ( ) ESRD or 2 x creatinine 1190 (38.2%) 1257 (40.2%) 0.94 ( ) Eze/simv better Placebo better

98 Proportional reduction in atherosclerotic event rate (95% CI) CTT: Effects on Major Atherosclerotic Events 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 32 mg/dl SHARP 17% risk reduction 0% Mean LDL cholesterol difference between treatment groups (mg/dl)

99 LIPIDS AND STATINS IN CKD Normal renal function: Statins improve egfr and reduce vascular events (GREACE, HPS, TNT, CARDS) Pre-dialysis: Ezetimibe + simvastatin reduces events but no change in renal function (SHARP) On-dialysis: Statins no improvement in events or renal function (4D, AURORA). Ezetimibe + simvastatin reduces events (SHARP)

100 Why was SHARP successful? n DM Duration HD AURORA: 2,776 20% 3.8 yrs ALL 4D: 1,255 ALL 4 yrs ALL SHARP: 9,270 23% 4.9 yrs 1/3* * No heterogeneity

101 Special conditions Pre-operative statins and CKD Post-transplant Contrast Induced Nephropathy (CIN)

102 CONCLUSIONS Dialysis: probably no statin benefit Early CKD: statin benefit CKD prevention: statin benefit Proteinuria/microalbuminuria

103 OTHER SPECIFIC GROUPS ONCOLOGY: Radiation to the heart Cytotoxic drugs and the heart Disease effects

104 OTHER SPECIFIC GROUPS AUTOIMMUNE DISEASES: SLE, RA, Psoriasis Effect on disease progression (symptoms, complications) Effect on inflammatory markers Effect on CV risk

105 OTHER SPECIFIC GROUPS TRANSPLANTATION: Lovastatin, atorvastatin, simvastatin CAUTION in patients on immunosuppressants (i.e. cyclosporine, sirolimus, tacrolimus) CYP3A4

106 Garshick M, Underberg JA. The Use of Primary Prevention Statin Therapy in Those Predisposed to Atherosclerosis. Curr Atheroscler Rep 2017; 19: 48

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