STATINS FOR PAD Long - term prognosis Prof. Pavel Poredos, MD, PhD Department of Vascular Disease University Medical Centre Ljubljana Slovenia
DECLARATION OF CONFLICT OF INTEREST No conflict of interest to declare
Atherosclerosis-systemic disease Atherosclerosis is considered a systemic disease, therefore subjects with proven atherosclerotic disease are likely to have similar or identical lesions in other vascular beds.
Atherosclerosis-systemic disease as atherosclerosis is considered a systemic disease it is expected that for different locations of atherosclerosis similar or identical RF are responsible for its development and that treatment of RF simultaneously influences atherosclerotic process in different sections of arterial bed (CHD, CVD, PAD) in contrast to CHD there are only a few data on the efficacy of preventive measures in PAD patients existing data on the efficacy of preventive measures in PAD patients and CVD are mostly gained from subgroup analysis of studies dedicated to CHD
Dyslipidemia and PAD dyslipidemia is one of most relevant RF of atherosclerosis and represents a major aspect of primary and secondary prevention of atherosclerosis hypercholesterolemia is a relevant RF not only for CHD but also for PAD benefit of lipid lowering therapy is proven in CHD, but there is less evidence regarding PAD
cholesterol level >7.0 mmol/l is associated with a doubling of the incidence of IC increase of total C for every 10 mg/dl is related to 10 % increase of risk for development of PAD Framingham Study, Circulation 1970
Patients with CHD event (%) Effects of lipid-lowering therapy on CV events in statin trials 25 20 15 10 5 0 HPS - S CARE - S 4S - S LIPID - S ASCOT - S * ASCOT - P * AFCAPS - S CARE - P HPS - P WOSCOPS - S LIPID - P 4S - P AFCAPS - P WOSCOPS - P 90 110 130 150 170 190 210 LDL-C (mg/dl) of LDL chol for 1 % - risk for CV events for 2 % Secondary Prevention Primary Prevention Simvastatin Pravastatin Lovastatin Atorvastatin S=statin treated P=placebo treated *Extrapolated to 5 years Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21.
Efficacy of cholesterol treatment in prevention of CV events Meta-analysis 90056 participants, 14 randomized trials Baigent et al. Lancet 2005
Relation between proportional reduction in incidence of CV events and mean cholesterol reduction Baigent et al. Lancet 2005
Statins and CV events Upgraduated meta-analysis 155.613 pts, 25-trials 14% reduction in major vascular events 11% reduction in mortality 16% reduction in major coronary events 10% reduction in strokes ------------------------------------------------------------------- Aggressive statin treatment improves cardiovascular outcomes compared with usual care Delahoy PJ et al., Clin Thor 2009
Effects of cholesterol treatment on CV events in PAD patients Incidence of coronary events in PAD patients and elevated LDL cholesterol for 5.4 years variable treated with statins (n=318) no treated with lipid lowering drugs (n=342) p value sudden coronary death 61 (19%) 106 (31%) 0,0005 fatal myocardial infarction 51 (16%) 84 (25%) 0,007 nonfatal myocardial infarction 41 (13%) 61 (18%) 0,079 new coronary events 153 (73%) 251 (73%) <0,0001 Willbert et al., Am J Cardiol 2002
Secondary prevention: effects of statins on CV events in PAD Data from HPS, Lancet 2002
HPS trial: main findings 6748 pts with PAD out of 20.536 participants Simvastatin safely reduced the risk of heart attack, of stroke, and of revascularization by at least one-third 5 years of statin treatment prevents: 70 major vascular events of every 1000 pts. with PAD 20% of non-coronary (peripheral) revascularization 16% in the rate of first PAD event appearance J Vasc Surg, 2008
Statins reduce perioperative morbidity and mortality in pts. with non-cardiac vascular surgery complication rate (AF, VT, MI, PE) after non-cardiac vascular surgery is high: average 5 10% in high risk pts. up to 34% Badner NH, Anesthesiology 1998 Poldermans D, N Engl J Med retrospective and prospective studies included more than 20.000 patients undergoing major vascular surgery: AAA repair, CEA, lower extremity revascularization Statins reduce perioperative morbidity and mortality up to 50 %. Benefit probably occurs soon after initiating treatment. Paraskevas KI, Eur J Vasc Endovasc Surg, 2006
Cholesterol lowering and its influence on PAD itself POSCH study (N=126) ileal by-pass reduced LDL cholesterol for 38% and 5 years incidence of IC was reduced for 42% Buchwald et al., N Engl J Med 1990 cholestipol niacin treatment decreased progression of femoral atherosclerosis in relation to decrease of LDL cholesterol (40% in 2 years) (N=153) Blankenhorn et al., Circulation 1991
Cholesterol lowering and regression of peripheral atherosclerosis CLAS study (% of FA lumen narrowing) % of patients 40 35 30 25 20 15 10 5 0 35 30 25 21 21 21 Regress No change Progress Drug Placebo Blankenhorn et al., Circulation 1991
Scandinavian Simvastatin Survival Study - 4 S Statins and new or worsening intermitent claudication 38 % risk reduction P = 0.013 Pedersen TR et al. Am J Cardiol 1998
PAD and statins hemodynamic effects Improvement of pain-free walking distance and quality of life in PAD pts during treatment with simvastatin 40mg, p<0.005 Mondillo, Am J Med 2003
Improvement of pain free walking time (PFWT) in 345 subjects treated with atorvastatin 80mg for 12 months (p<0.025) Mohler, et al., Circulation 2003
Functional outcomes in subjects with normal or pathological ABI according to statin use ---------------------------------------------------------------------------------------- ABI <0.90 (n=392) ABI 0.90 to 1.50 (n=249) ABI 1.50 (n=541) --------------------------------------- ------------------------------------- --------------------------------------- statin statin statin statin statin statin users nonusers users nonusers users nonusers (n=177) (n=215) P (n=75) (n=174) P (n=252) (n=389) P -------------------------------------------------------------------------------------------------------------------------------------------------------- 6 min. walk 1159 (369) 1098 (375) 0.109 1456 (389) 1414 (425) 0.447 1247 (398) 1239 (427) 0.808 distance (feet) 4 min. walk. 0.90 (0.18) 0.86 (0.22) 0.057 0.98 (0.18) 0.93 (0.22) 0.079 0.92 (0.19) 0.89 (0.22) 0.060 velocity (m/s) summary 10.1 (2.1) 9.0 (2.8) <0.001 10.6 (1.8) 10.0 (2.4) 0.055 10.2 (2.1) 9.4 (2.7) <0.001 performance score (range, 0 to 12, 12=best) ------------------------------------------------------------------------------------------------------------------------------------------------------- Better leg functioning in statin users that was independent on cholesterol level.
Participants with and without peripheral arterial disease absence of statin use ----------------------------------------------------------------------------------------------------------------------------- ------ PAD Non-PAD N=332 N=212 ---------------------------------------- -------------------------------------------- statins users non-users statin users non-users (n = 152) (n = 180) (n = 61) (n = 151) ----------------------------------------------------------------------------------------------------------------------------- ------ age (yrs) 70.9 (7.7) 72.1 (9.1) 69.2 (7.5) 69.6 (8.3) ankle brachial index 0.66 (0.14) 0.64 (0.15) 1.08 (0.10) 1.11 (0.12) total cholesterol 171 (37.6) 188 (37.4) 165 (32.2) 182 (38.1) Functional performance 6 min. walk dist. (ft) 1185 (361) 116 (375) 1466 (442) 1408 (446) normal-pace 4-m-walk.velocity (m/s) 0.915 (0.179)ϯϯ 0.859 (0.228) 0.990 (0.192) 0.941 (0.216) normal-pace 4-m walk. time (s) 4.55 (1.00)# 5.05 (2.08) 4.23 (1.09) 4.61 (1.79) (m/s) rapid-pace 4-m walk. velocity ( 0.231 ) 1.258 (0.297) 1.184 (0.262) 1.316 (0.304) 1.287 rapid-pace 4-m walk. time (s) 3.31 (0.76) 3.70 (1.50) 3.19 (0.80) 3.41 (1.58) summary performance score 10.2 (2.0)## 9.2 (2.9) 10.6 (2.1)*** 10.0 (2.6) (9 to 12 score,12=best) -------------------------------------------------------------------------------------------------------------------------------------------------------- Giri J et al., J Am Coll Cardiol, 2006
Main effects of treatment of PAD patients with statins prevention of progression of peripheral atherosclerotic lesions improvement of walking capacity and quality of life in patients with intermittent claudication prevention of coronary or cerebrovascular incidents and improvement of prognosis of PAOD patients
ACC/AHA GUIDELINES RECOMMENDATIONS Class I Treatment with a hydroxymethyl (HMG) coenzyme-a reductase inhibitor (statin) medication is indicated for all patients with PAD to achieve a target LDL cholesterol level less than 100 mg per dl (level of Evidence: B) Class II a Treatment with a HMG coenzyme-a reductase inhibitor (statin) medication to achieve a target LDL cholesterol level of less than 70 mg per dl is reasonable for patients with lower extremity PAD at very high risk of ischemic events (level of Evidence: B)
TREATMENT PARADOX PAD is a marker of systemic atherosclerosis and this patients are at high risk for CV incidents but only 44 % of PAD patients receive lipid lowering intervention PAD patients are underdiagnosed and undertreated PARTNERS Study