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Lipid Management: Case by Case
3:00 p.m. Unusual Vascular Diseases: Takayasu's, Giant CelI Arteritis, Thromboangiitis Obliterans, and Fibromuscular Dysplasia Thom Rooke, MD Mayo Clinie Roehester, MN
3:30 p.m. Panel Discussion
3:50 p.m. Break
4:05 p.m. Lipid Management: Case by Case Emile R. Mohler, 1l1D University oj Pennsy/vania Presbyterian Mediea/ Center Philadelphia, PA Patients with dyslipidemia are at increased risk for the development ofPAD and its manifestations including IC, as well as graft occlusion. Several lipid fractions confer an increased risk of PAD including elevations of total cholesterol (1-3) low-density lipoprotein cholesterol (LDL-C), triglycerides (2), and Iipoprotein(a) (Lp(a)) (4,5) lt is estimated that for evely 10 mg/dl increase in total cholesterol concentration, the risk for developing PAD increases approximately 10% (6). Similarly, results from epidemiological srudies indicate that elevated LDL-C increases the likelihood of developing PAD. Patients with relative elevation in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-l have a reduced incidence of PAD (5). Mowat and colleagues found that in their population, PAD patients had higher levels of triglycerides and very low-density lipo protein concentrations, as weJl as low HDL-C (7). Patients with familial dysbetalipoproteinemia (familial type III hyperJipidemia) have a structural defect in apo E and accumulate remnants of VLDL and chylomicrons in plasma due to defective binding to receptors within the Iiver (8). Tendinous and tuberous xanthomas can develop and the lipid profile is typically such that the cholesterol and triglycerides are e1evated lO the same degree. These individuals have a propensity for early onset PAD. Thus, in addition to elevated total cholesterol, study results suggest that elevated triglycerides and low HDL-C contribute to the development of peripheral atherosclerosis. Unfortunately, there is no published prospective, randomized controlled study of cholesterol reduction and evaluation of cardiovascular events in patients with PAD. However, there is a large amOUnL of published data indicating a reduction of LDL-C in this patient population is likely beneficia!. Blankenhorn and colleagues conducted a prospective stuely that evaluated femoral ath-
erosclerosis by angiography (performed at baseline and one year later) in patients receiving cholesterol-reducing therapy with a combination of colestipol and niacin (9). The annual rate of change in computer-estimated atherosclerosis, a measure of lumen abnormality, was evaluated between treatment groups. There was a significant treatment effect in segments wit h moderately severe atherosclerosis (P < .04) and in proximal segments (P < .02) (9). Another human angiographic study, the Probucol Quantitative Regression Swedish Trial (PQRSD was designed to evaluate if the addition of probucol to a eliet low in cholesterol and treatment with cholestyramine retarded progression of femoral atherosclerosis (10). In this study, the adelition of probucol diel not resuJt in significant regression of atherosclerosis compared to the cholestyramine treateel group. The Program On Surgical Control of Hyperlipidemia (POSCH) Study revealed that i1eal bypass surgery reeluceel LDL-C levels in patients who had suffered a myocarelial infarction. Patients who received ileal bypass surgely had a reduced incidence of hemodynamically significant PAD compared to the control group, 44% vs. 30%, respectively (11). The Scandinavian Simvastatin Survival Study (4S) was a secondary prevention trial in patients who had a myocardial infarction and was aimed at demonstrating whether statin therapy can reduce both total mortality and cardiovascular mortality (12). In this trial, simvastatin reduced LDL-C by 35%, increased HDL-C by 8% and reduced major coronaly events and total mortality by 42% and 30%, respectively. A post-hoc analysis of the data revealed that patients treated with statin therapy had less new or worsening IC (38%) than patients that received placebo (P = .008) (13). A stuely by Kroon and colleagues evaluated patients with CAD and elevations in total cholesterol and Lp(a) after receiving treatment with simvastatin therapy alone ar sinwastatin willi bi-weekly apheresis (4). The group that received simvastatin alone had no effect on Lp(a) levels, whereas the combination of simvastatin with apheresis reduced Lp(a) levels by 20%. Simvastatin therapy alone diel not prevent an increase in the number of occlusive lesions in leg vessels over time. In contrast, simvastatin plus apheresis decreased the accumulation of atherosclerotic lesions. This stuely suggests thal lowering Lp(a) concentrations reduces the progression of PAD. Recently, the Heart Protection Study confirmed that lipid lowering therapy with a statin reduces the risk of death and adverse cardiovascular events in patients with coronary and noncoronary atherosclerosis, including peripheral arterial disease (15). In conclusion, patients with PAD are at high risk for cardiovascular events and lipid-modifying therapy likely will reeluce the progression of PAD and cardiovascular events. The National Cholesterol Education Program III
P29
(NCEP-III) guidelines recommend the target goal of LDL-C reduction to less than 100 mg/dl for patients with PAD (16). Therapy may include a combination of diet, exercise and Iipid-modifying agents, although statin drugs are usually required to achieve the target LDL-C level. References 1. Gofin R, Kark JD, Friedlander Y, Lewis BS, Witt H, Stein Y, et al. PeripheraJ vascular disease in a middle-aged population sample. The Jerusalem Lipid Research Clinic Prevalence Study. Isr J Med Sci 1987; 23:157-167. 2. Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978; 1:1379-1381. 3. Bowlin SJ, MedalieJH, Flocke SA, Zyzanski SJ, Goldbourt U. Epidemiology of intermittent claudication in middle-aged men. AmJ Epidemiol1994; 140:418430 4. Cantin B, Moorjani S, Dagenais GR, Lupien P]. Lipoprotein(a) distribution in a French Canadian population and its relation to intermittent claudication (the Quebec Cardiovascular Study). Am J Cardiol 1995; 75:1224-1228. 5. Johansson J, Egberg N, Johnsson H, Carlson LA. Serum Iipoproteins and hemostatic function in intermittent claudication. Arterioscler Thromb 1993; 13: 1441-1448. 6. Hiatt WR, Hoag S, Hamman Rf. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circ 1995; 91:1472-1479. 7. Mowat BF, Skinner ER, Wilson HM, Leng GC, Fowkes FG, Horrobin D. Alterations in plasma Iipids, Iipoproteins and high density lipoprotein subfractions in peripheral arteriaI disease. Athero 1997; 131:161-166. 8. Brewer HB, Jr., Zech LA, Gregg RE, Schwartz D, Schaefer E]. NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment. Ann Intern Med 1983; 98:623-640. 9. Blankenhorn DH, Azen SP, Crawford DW, Nessim SA, Sanmarco ME, Selzer RH et al. Effects of colestipol-niadn therapy on human femoral atherosclerosis. Circlllation 1991; 83:438-447. 10. Walldius G, Erikson U, Olsson AG, Bergstrand L, Hadell K, Johansson J et al. The effect of probucol on femoral atherosclerosis: the Probllcol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol 1994; 74:875-883. 11. Buchwald H, BOUl·dages HR, Campos CT, Nguyen P, Williams SE, Boen JR. Impact of cholesterol reduction on peripheral arterial disease in the Program on
P30
the Surgical Control of the Hyperlipidernias (paSCH). Surgery 1996; 120:672- 679. 12. Scandinavian Simvistatin SlIlvival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Stlldy (4S). Lancet 1994; 344: 1383-1389. 13. Pedersen TR, Kjekshus J, Pyorala K, 01sson AG, Cook TJ, Musliner TA, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin su rviva I study (4S). Am J CardioJ 1998; 81:333--335. 14. Kroon AA, van Asten WN, Stalenhoef AP. Effect of apheresis of low-density lipoprotein on peripheral vascular disease in hypercholesterolemic patients with coronary artely disease. Ann Intern Med 1996; 125:945-954. 15. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 20,536 high-risk individuais: a randomised placebo-controlled trial. Lancet 2002; 360:7-22. 16. Executive Summary of The Third Report of The National Cholesterol Edllcation Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adllit Treatment Panel III). JAMA 2001; 285:2486-2497 4:40 p.m. Wound Care Principles: Heal It or Lose It Thom Rooke, MD Mayo Clinic Rochester, MN 5:05 p.m. Hypercoagulable Workup: When and How to Initiate j. Michael Bacha/"ach, MD, MPH, FACC North Central Heart lnstitute Sioux Fal!s, SD Defining the Problem Hypercoagulability is a condition in which persons are unusually predisposed to thrombotic events as a resuJt of inherited and/or acquired defects in the natural mechanism of coagulation system. Classification Classification of the hypercoagulable patient is divided into two basic categories. The first is genetic and the second acquired. aur knowledge of genetic disorders has increased substantially in the past decade. Discovery of factor V Leiden and prothrombin G20210A mutation has greatly increased the number of patients we can attribute to hereditary causes. Common genetic or hereditary causes of hypercoagulability include:
3:30 p.m. Panel Discussion
3:50 p.m. Break
4:05 p.m. Lipid Management: Case by Case Emile R. Mohler, 1l1D University oj Pennsy/vania Presbyterian Mediea/ Center Philadelphia, PA Patients with dyslipidemia are at increased risk for the development ofPAD and its manifestations including IC, as well as graft occlusion. Several lipid fractions confer an increased risk of PAD including elevations of total cholesterol (1-3) low-density lipoprotein cholesterol (LDL-C), triglycerides (2), and Iipoprotein(a) (Lp(a)) (4,5) lt is estimated that for evely 10 mg/dl increase in total cholesterol concentration, the risk for developing PAD increases approximately 10% (6). Similarly, results from epidemiological srudies indicate that elevated LDL-C increases the likelihood of developing PAD. Patients with relative elevation in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-l have a reduced incidence of PAD (5). Mowat and colleagues found that in their population, PAD patients had higher levels of triglycerides and very low-density lipo protein concentrations, as weJl as low HDL-C (7). Patients with familial dysbetalipoproteinemia (familial type III hyperJipidemia) have a structural defect in apo E and accumulate remnants of VLDL and chylomicrons in plasma due to defective binding to receptors within the Iiver (8). Tendinous and tuberous xanthomas can develop and the lipid profile is typically such that the cholesterol and triglycerides are e1evated lO the same degree. These individuals have a propensity for early onset PAD. Thus, in addition to elevated total cholesterol, study results suggest that elevated triglycerides and low HDL-C contribute to the development of peripheral atherosclerosis. Unfortunately, there is no published prospective, randomized controlled study of cholesterol reduction and evaluation of cardiovascular events in patients with PAD. However, there is a large amOUnL of published data indicating a reduction of LDL-C in this patient population is likely beneficia!. Blankenhorn and colleagues conducted a prospective stuely that evaluated femoral ath-
erosclerosis by angiography (performed at baseline and one year later) in patients receiving cholesterol-reducing therapy with a combination of colestipol and niacin (9). The annual rate of change in computer-estimated atherosclerosis, a measure of lumen abnormality, was evaluated between treatment groups. There was a significant treatment effect in segments wit h moderately severe atherosclerosis (P < .04) and in proximal segments (P < .02) (9). Another human angiographic study, the Probucol Quantitative Regression Swedish Trial (PQRSD was designed to evaluate if the addition of probucol to a eliet low in cholesterol and treatment with cholestyramine retarded progression of femoral atherosclerosis (10). In this study, the adelition of probucol diel not resuJt in significant regression of atherosclerosis compared to the cholestyramine treateel group. The Program On Surgical Control of Hyperlipidemia (POSCH) Study revealed that i1eal bypass surgery reeluceel LDL-C levels in patients who had suffered a myocarelial infarction. Patients who received ileal bypass surgely had a reduced incidence of hemodynamically significant PAD compared to the control group, 44% vs. 30%, respectively (11). The Scandinavian Simvastatin Survival Study (4S) was a secondary prevention trial in patients who had a myocardial infarction and was aimed at demonstrating whether statin therapy can reduce both total mortality and cardiovascular mortality (12). In this trial, simvastatin reduced LDL-C by 35%, increased HDL-C by 8% and reduced major coronaly events and total mortality by 42% and 30%, respectively. A post-hoc analysis of the data revealed that patients treated with statin therapy had less new or worsening IC (38%) than patients that received placebo (P = .008) (13). A stuely by Kroon and colleagues evaluated patients with CAD and elevations in total cholesterol and Lp(a) after receiving treatment with simvastatin therapy alone ar sinwastatin willi bi-weekly apheresis (4). The group that received simvastatin alone had no effect on Lp(a) levels, whereas the combination of simvastatin with apheresis reduced Lp(a) levels by 20%. Simvastatin therapy alone diel not prevent an increase in the number of occlusive lesions in leg vessels over time. In contrast, simvastatin plus apheresis decreased the accumulation of atherosclerotic lesions. This stuely suggests thal lowering Lp(a) concentrations reduces the progression of PAD. Recently, the Heart Protection Study confirmed that lipid lowering therapy with a statin reduces the risk of death and adverse cardiovascular events in patients with coronary and noncoronary atherosclerosis, including peripheral arterial disease (15). In conclusion, patients with PAD are at high risk for cardiovascular events and lipid-modifying therapy likely will reeluce the progression of PAD and cardiovascular events. The National Cholesterol Education Program III
P29
(NCEP-III) guidelines recommend the target goal of LDL-C reduction to less than 100 mg/dl for patients with PAD (16). Therapy may include a combination of diet, exercise and Iipid-modifying agents, although statin drugs are usually required to achieve the target LDL-C level. References 1. Gofin R, Kark JD, Friedlander Y, Lewis BS, Witt H, Stein Y, et al. PeripheraJ vascular disease in a middle-aged population sample. The Jerusalem Lipid Research Clinic Prevalence Study. Isr J Med Sci 1987; 23:157-167. 2. Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978; 1:1379-1381. 3. Bowlin SJ, MedalieJH, Flocke SA, Zyzanski SJ, Goldbourt U. Epidemiology of intermittent claudication in middle-aged men. AmJ Epidemiol1994; 140:418430 4. Cantin B, Moorjani S, Dagenais GR, Lupien P]. Lipoprotein(a) distribution in a French Canadian population and its relation to intermittent claudication (the Quebec Cardiovascular Study). Am J Cardiol 1995; 75:1224-1228. 5. Johansson J, Egberg N, Johnsson H, Carlson LA. Serum Iipoproteins and hemostatic function in intermittent claudication. Arterioscler Thromb 1993; 13: 1441-1448. 6. Hiatt WR, Hoag S, Hamman Rf. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circ 1995; 91:1472-1479. 7. Mowat BF, Skinner ER, Wilson HM, Leng GC, Fowkes FG, Horrobin D. Alterations in plasma Iipids, Iipoproteins and high density lipoprotein subfractions in peripheral arteriaI disease. Athero 1997; 131:161-166. 8. Brewer HB, Jr., Zech LA, Gregg RE, Schwartz D, Schaefer E]. NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment. Ann Intern Med 1983; 98:623-640. 9. Blankenhorn DH, Azen SP, Crawford DW, Nessim SA, Sanmarco ME, Selzer RH et al. Effects of colestipol-niadn therapy on human femoral atherosclerosis. Circlllation 1991; 83:438-447. 10. Walldius G, Erikson U, Olsson AG, Bergstrand L, Hadell K, Johansson J et al. The effect of probucol on femoral atherosclerosis: the Probllcol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol 1994; 74:875-883. 11. Buchwald H, BOUl·dages HR, Campos CT, Nguyen P, Williams SE, Boen JR. Impact of cholesterol reduction on peripheral arterial disease in the Program on
P30
the Surgical Control of the Hyperlipidernias (paSCH). Surgery 1996; 120:672- 679. 12. Scandinavian Simvistatin SlIlvival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Stlldy (4S). Lancet 1994; 344: 1383-1389. 13. Pedersen TR, Kjekshus J, Pyorala K, 01sson AG, Cook TJ, Musliner TA, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin su rviva I study (4S). Am J CardioJ 1998; 81:333--335. 14. Kroon AA, van Asten WN, Stalenhoef AP. Effect of apheresis of low-density lipoprotein on peripheral vascular disease in hypercholesterolemic patients with coronary artely disease. Ann Intern Med 1996; 125:945-954. 15. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 20,536 high-risk individuais: a randomised placebo-controlled trial. Lancet 2002; 360:7-22. 16. Executive Summary of The Third Report of The National Cholesterol Edllcation Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adllit Treatment Panel III). JAMA 2001; 285:2486-2497 4:40 p.m. Wound Care Principles: Heal It or Lose It Thom Rooke, MD Mayo Clinic Rochester, MN 5:05 p.m. Hypercoagulable Workup: When and How to Initiate j. Michael Bacha/"ach, MD, MPH, FACC North Central Heart lnstitute Sioux Fal!s, SD Defining the Problem Hypercoagulability is a condition in which persons are unusually predisposed to thrombotic events as a resuJt of inherited and/or acquired defects in the natural mechanism of coagulation system. Classification Classification of the hypercoagulable patient is divided into two basic categories. The first is genetic and the second acquired. aur knowledge of genetic disorders has increased substantially in the past decade. Discovery of factor V Leiden and prothrombin G20210A mutation has greatly increased the number of patients we can attribute to hereditary causes. Common genetic or hereditary causes of hypercoagulability include: