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Untitled-Management of Peripheral Arterial Disease
DANIELA C. GEY, M.D., University of Heidelberg School of Medicine, Heidelberg, Germany
EMIL P. LESHO, LTC, MC, USA, U.S. Army Medical Department Activity, Heidelberg, Germany
JOHANNES MANNGOLD, M.D., Kreuzlingen Heart Center, Bodensee, Switzerland
Peripheral arterial disease is common, but the diagnosis frequently is overlooked
because of subtle physical findings and lack of classic symptoms. Screening based on the
ankle brachial index using Doppler ultrasonography may be more useful than physical
examination alone. Noninvasive modalities to locate lesions include magnetic resonance
angiography, duplex scanning, and hemodynamic localization. Major risk factors for
peripheral arterial disease are cigarette smoking, diabetes mellitus, older age (older than
40 years), hypertension, hyperlipidemia, and hyperhomocystinemia. Nonsurgical therapy
for intermittent claudication involves risk-factor modification, exercise, and pharmaco-
logic therapy. Based on available evidence, a supervised exercise program is the most
effective treatment. All patients with peripheral arterial disease should undergo aggres-
sive control of blood pressure, sugar intake, and lipid levels. All available strategies to
help patients quit smoking, such as counseling and nicotine replacement, should be
used. Effective drug therapies for peripheral arterial disease include aspirin (with or
without dipyridamole), clopidogrel, cilostazol, and pentoxifylline. (Am Fam Physician
2004;69:525-32,533. Copyright 2004 American Academy of Family Physicians.)
may thwart effective secondary preven-tive strategies,2 including intensive treat-ment for hyperlipidemia, hypertension, arterial disease (PAD) affects approximately 12 million persons in the and smoking cessation. [Evidence level C, study1 concluded that many physicians routinely do not obtain a relevant his- Important Signs of Chronic
subtle signs of the condition on physi-cal examination (Tables 1 and 2). The underdiagnosis of PAD in primary care Limb examination (and comparison with the opposite limb) includes: Poor nail growth (brittle nails)Dry, scaly, atrophic skin Differential Diagnosis
of Intermittent Claudication
Pallor with leg elevation after one minute at 60 degrees (normal color should return in Nonvascular causes
10 to 15 seconds; longer than 40 seconds Ischemic tissue ulceration (punched-out, pulses (especially after exercising the limb) Vascular causes
Additional examination by palpation and aus- Thromboangiitis obliterans (Buerger’s disease) cultation to detect abnormal aortic aneurysm See page 465 for defi-nitions of strength-of-evidence levels. Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2004 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact firstname.lastname@example.org for copyright questions and/or permission requests.
patients with PAD may not have the clas-sic symptoms of claudication.3 Some experts FIGURE 1. Dermatologic findings of peripheral argue that a thorough physical examination with special attention to the pulses, auscul-tation for arterial bruits, and inspection for Diagnosis
postural color changes (Figure 1) can be almost as informative as an ABI using Dop- Screening based on the ankle brachial index Several factors complicate the diagnosis phy could prove highly useful in identifying patients with previously unrecognized PAD.2 proximal aneurysm or arterial occlusive dis- In a recent multicenter study,3 the ABI corre- ease distal to the ankle.4 Obtaining a medical lated more closely with exercise capacity than history also can be problematic.1,5 Although did symptoms. This finding implies that many 83 percent of the patients in one large study2 knew they had PAD, only 49 percent of their physicians were aware of this history. More than one half of patients identified as having PAD on the basis of an abnormal ABI value do not have typical claudication symptoms, but they do have other types of leg pain on exertion, with reduced ambulatory activity and quality of life.3 dication or other symptoms if the occlusion develops slowly, allowing sufficient collateral circulation to develop, or if the patient is mostly sedentary.4 Improving skills in eliciting symptoms, examining the peripheral vascular system, and obtaining segmental blood pres-sures (Figure 2),6 plus increased use of Doppler ABI in patients at risk of PAD, should identify more patients in whom aggressive preventive strategies might delay disease progression or obviate the need for an invasive interven-tion.1,2 Treatment
dication involves risk-factor modification, FIGURE 2. Segmental blood pressure measurement. A, segmental leg exercise training, and pharmacologic therapy pressures in a normal right extremity (ABI: 115/115 = 1.00) and one with an isolated left iliac artery occlusion (ABI: 70/117 = 0.60). Horizontal and vertical pressure gradients exist at the thigh. B, segmental leg pressures RISK-FACTOR MODIFICATION
in a patient with an isolated focal right superficial femoral artery steno- sis and a distal left tibial artery occlusion. (ABI = ankle brachial index) hypertension, hyperlipidemia, age older than Adapted with permission from Wilt TJ. Current strategies in the diagnosis and 40 years, and hyperhomocystinemia increase management of lower extremity peripheral vascular disease. J Gen Intern Med 1992;7:91. the risk of developing PAD. All patients with PAD, regardless of the severity of symptoms, should undergo risk-factor modification. Currently, almost one fourth of adults in Smoking. Smoking is the most important the United States smoke cigarettes, and 70 risk factor and is correlated more closely percent of smokers report that they want to quit.9 Approximately one third of smokers factor.7 Smoking cessation probably reduces try to stop smoking each year, but only 20 the severity of claudication; however a meta- percent seek professional help. Fewer than 10 analysis8 concluded that it did not improve percent of smokers who attempt to quit on maximal treadmill walking distance. [Evi- their own are successful over the long term.9 dence level B, observational study] Cessation Two approaches have strong evidence of effi- of cigarette smoking reduces the progression cacy for smoking cessation: pharmacotherapy of disease, as shown by lower rates of amputa- and counseling.9-11 Each is effective by itself, tion and lower incidences of rest ischemia in but the two combined achieve the highest patients who quit, and it reduces the risks of rates of smoking cessation.9,11 Clinical trials myocardial infarction and death from other have demonstrated that a physician’s advice Management of Peripheral Arterial Disease
Assess for peripheral arterial disease.
profiles, hypertension, diabetes, hypercoagulability screen, homocysteine level, Lp(a) lipoprotein (A1c <7.0 percent), smoking cessation (counseling and pharmacotherapy), hypertension treatment (follow JNC-VI guidelines), LDL cholesterol <100 mg per dL (2.60 mmol per L), antiplatelet scanning, hemodynamic localization, MRA, angiography.
FIGURE 3. Algorithm for the evaluation and management of patients with peripheral arte- rial disease. (MWD = maximal walking distance; PFWD = pain-free walking distance; SF-36 = medical outcomes short form 36 questionnaire; WIQ = walking impairment questionnaire; A1c = hemoglobin A1c; JNC-VI = Sixth report of the Joint National Committee on Prevention, Detec- tion, Evaluation, and Treatment of High Blood Pressure; LDL = low-density lipoprotein; MRA = to stop smoking increases the rates of smok- tight glycemic control decreases the incidence ing cessation in patients by approximately of intermittent claudication or critical limb 30 percent.12 Providing a brief three-min- ischemia.13 However, minimizing hypergly- ute counseling session is more effective than cemia as a risk factor associated with the sub- advising the patient to quit, and it doubles sequent development of PAD could not only the cessation rate compared with no interven- decrease the rates of cardiovascular disease tion.12 Too often, physicians miss this critical and myocardial infarction, but also reduce the comes (claudication, peripheral revascular- (FDA) has approved six products for smok- ization, or critical limb ischemia and ampu- ing cessation: sustained-release bupropion (Zyban) and five nicotine-replacement prod- ucts (i.e., gum, lozenge, a transdermal patch, Intensive insulin therapy elicited a trend a nasal spray, and a vapor inhaler). The use for reduced risk of important PAD outcomes of all nicotine-replacement products increases (claudication, peripheral revascularization, or the long-term rates of smoking cessation and amputation) by 22 percent. This result did relieves cravings for nicotine and the symp- not achieve statistical significance, because toms of nicotine withdrawal. Nortriptyline the study was not powered for assessment of (Pamelor) and clonidine (Catapres) also have this outcome. In other words, there is at least been found to aid smoking cessation, but the moderately strong, if statistically inconclusive, FDA has not approved them for this indica- evidence that macrovascular coronary (and potentially limb) outcomes are improved with Diabetes Mellitus. No controlled trials have glycemic control, and these outcomes are directly evaluated the effects of antidiabetic central to good PAD care. Even in the absence therapy on the natural history of PAD. Cur- of high-quality clinical investigations, it is rently, no prospective evidence shows that important to note that diabetic control has an impact on limb infection and amputation in patients with severe PAD (critical limb ischemia). Furthermore, because aggressive DANIELA C. GEY, M.D., is a dermatology resident at the human immunodeficiency control of blood glucose in type 1 and type virus (HIV)/sexually transmitted disease clinic affiliated with the University of Heidel- 2 diabetes reduces the risk of microvascular berg School of Medicine, where she received her medical degree. She is an investigator in two international, multicenter studies of immune augmentation with interleukin-2 complications, it also may benefit patients in patients with HIV or acquired immunodeficiency syndrome, and has participated in other research projects investigating experimental protease inhibitors.
Hypertension. Hypertension is a major risk EMIL P. LESHO, LTC, MC, USA, is currently an infectious diseases fellow at the National factor for PAD, but the effect of antihyper- Capital Consortium, Uniformed Services University of the Health Sciences, National tensive therapy on the progression of disease Naval Medical Center, Bethesda, Md., and Walter Reed Army Medical Center, Wash-ington, D.C. Dr. Lesho received his medical degree from Philadelphia College of or the risk of claudication is unclear. Data Osteopathic Medicine and completed an internal medicine residency at Madigan Army derived from studies of cardiovascular disease Medical Center, Tacoma, Wash. He was formerly with the Army Medical Department support the aggressive treatment of hyperten- sion in patients with PAD.7 Although no data JOHANNES MANNGOLD, M.D., is a first-year resident in internal medicine at the Kreuz- demonstrate an impact of antihypertensive lingen Heart Center, Bodensee, Switzerland. He completed his undergraduate and medical school training at the University of Heidelberg School of Medicine, Heidelberg, therapy on PAD outcomes, this lack of data is because PAD-related event rates are low. The Address correspondence to Emil P. Lesho, LTC, MC, USA, 611 Forest Glen Rd., Silver power to detect such outcomes would require Spring, MD 20901 (e-mail: email@example.com). Reprints are not available from a trial larger than the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) effort, and a trial of efficacy would ethically require an active comparator intervention, making the Exercise training is the most effective treatment of peripheral assessment of PAD-specific and drug-specific Hypertension should be controlled in these patients primarily to reduce morbidity from cardiovascular and cerebrovascular disease. min B12 metabolism, and dietary folate defi- The use of beta blockers in patients with inter- ciency. Although supplementing the diet with mittent claudication was of concern because B vitamins and folate usually lowers serum several early case reports documented wors- homocysteine concentrations,27 no controlled ening claudication and decreasing blood flow trials demonstrate that reducing serum homo- in the legs of patients taking these drugs. A cysteine concentration is beneficial in patients later meta-analysis and critical review con- with PAD.28 PAD is not a contraindication to cluded that beta-adrenergic antagonists are estrogen therapy, but estrogen should not be safe in patients with PAD, except in those recommended for treating PAD in postmeno- most severely affected. Even in these patients, the drugs can be administered, but with cau-tion.15,16 Hyperlipidemia. Several large clinical tri- Exercise. A formal exercise program is als have demonstrated the benefits of lipid- the most effective treatment of PAD, and lowering therapy in patients with PAD who effectiveness was demonstrated in more than have coexisting coronary and cerebral arterial 20 controlled trials.30-33 Exercise increased disease.17-25 Simvastatin (Zocor) drastically the distance to onset of claudication by 179 lowered cardiovascular ischemic event rates percent in a meta-analysis of 21 published in the large PAD subgroup, despite initial low studies.33 The greatest improvements in walk- low-density lipoprotein (LDL) levels.25 Lipid ing ability occur when each exercise session normalization has been shown to reduce dis- lasts longer than 30 minutes, when sessions ease progression and the severity of claudica- take place at least three times per week, when tion.17-25 The current recommendation for the patient walks until near-maximal pain patients is to achieve a serum LDL cholesterol is reached in each session, and when the concentration of less than 100 mg per dL program lasts at least six months.33 These (2.6 mmol per L) and a serum triglyceride improvements were sustained when patients concentration of less than 150 mg per dL continued to participate in a maintenance (3.9 mmol per L).18 A statin drug should be given as initial therapy, but niacin also is a Another meta-analysis34 from the Cochrane consideration because it increases serum high- Collaboration that considered only random- density lipoprotein (HDL) concentrations and ized controlled trials showed that exercise lowers serum triglyceride concentrations with- produced significant improvements in walk- out (as formerly believed) worsening glucose antiplatelet therapy. Motivated patients in Hyperhomocystinemia. A high serum homo- a supervised setting modeled after cardiac cysteine concentration is an independent risk rehabilitation had the best results.33 The large, factor for PAD and is associated with an exercise-induced improvements in function increased risk of death from cardiovascular and symptoms that occur in patients with causes.26 The causes of high serum homocys- claudication do not appear to be caused by teine concentrations include genetic defects in an increased collateral blood flow but by homocysteine metabolism, alterations in vita- other mechanisms.33 Such potential mecha- TABLE 3
Pharmacotherapy for Patients with Claudication
Recommended by the American College of Chest Physicians for PAD, but the FDA found insufficient evidence to approve labeling for this indication Fewer side effects than aspirin in the CAPRIE trial; significantly less risk for TTP than ticlopidine May have a small effect on walking ability, but insufficient data to support widespread use Correct dosing is critical; avoid in patients with heart failure; reduce dosing to 50 mg twice per day in patients taking calcium channel blockers; may 500 mg per day orally Extensive hemodynamic monitoring for risk of TTP 600 mg per day orally Serotonin antagonist; increased walking distance in several trials, but use remains controversial; iloprost, prostaglandin E1 orally, or 60 mcg [Alprostadil]) Promising results in uncontrolled trials Effective, but study methodology questionable PAD = peripheral arterial disease; FDA = U.S. Food and Drug Administration; CAPRIE = Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; TTP = thrombotic thrombocytopenic purpura. nisms include improvements in endothelial reactions and because of the availability of vasodilator function, inflammatory responses, newer safer agents (Table 3). Aspirin and skeletal-muscle metabolism, enhanced oxy- dipyridamole (Persantine) increase the pain- gen availability by improved blood viscosity, free walking distance and resting limb blood and lessened ischemia at any achieved work- flow, or lead to an improved coagulation The recent publication of a current proce- In the Clopidogrel versus Aspirin in Patients dural terminology (CPT) code for PAD exer- at Risk of Ischemic Events (CAPRIE) trial,36 cise reflects the importance of exercise therapy 75 mg of clopidogrel was slightly but sig- nificantly better than 325 mg of aspirin in Terminology, American Medical Association, the total population for preventing strokes, myocardial infarction, and vascular disease.36 Pharmacologic Therapy. Although a meta- The PAD subgroup with nearly 6,500 patients analysis of randomized studies of antiplatelet agents found that ticlopidine (Ticlid) had spective PAD clinical trial and demonstrated the best evidence of efficacy in improvement a profound superiority in the PAD popula- in walking distance and reduction in occlu- tion treated with clopidogrel compared with sion,7,28 it is no longer used because it has been aspirin alone.36 This result led to the FDA associated with life-threatening hematologic approval of clopidogrel (Plavix) for the sec- ondary prevention of atherosclerotic events in patients with PAD.
National guidelines currently recommend aspirin (with or Pentoxifylline (Trental), a rheologic modi- without dipyridamole) or clopidogrel as first-choice drugs for fier that also has an antiplatelet effect, was approved in 1984 for the treatment of clau-dication. Pentoxifylline is less effective than cilostazol (Pletal).28,35 Two meta-analyses and two systematic reviews of pentoxifylline con- in Europe, macrolide antibiotic treatment for cluded that although the drug may have a chlamydia infection, propionyl levocarnitine, small effect on walking ability, the data are defibrotide, ginkgo biloba, hyperbaric oxy- insufficient to support its widespread use.28,35 gen, and angiogenic growth factors. Of these, In a more recent controlled trial,36 pent- angiogenic growth factors are perhaps the oxifylline was significantly superior to placebo most promising.35 For an in-depth, evidence- in improving walking distance after six and based review of PAD management, physicians may refer to the Trans Atlantic Inter-Society Cilostazol inhibits phosphodiesterase 3, sup- presses platelet aggregation, activates lipopro-tein lipase, and causes arterial dilation.7,28,35 The authors indicate that they do not have conflicts Approved in 1999 by the FDA for the treat- of interest. Sources of funding: none reported. ment of claudication, it improved pain-free The opinions and assertions contained herein are and maximal treadmill walking distance in the private views of the authors and are not to be randomized controlled trials compared with construed as official or as reflecting the views of the placebo or pentoxifylline.7,28,35 Correct dos- U.S. Army Medical Department or the U.S. Army ing is important, because 100 mg orally twice per day significantly improved claudication symptoms, while 100 mg per day did not.38 Cilostazol should not be used in patients 1. Ouriel K. Detection of peripheral arterial disease in with heart failure.7,28 The dosage should be 2. Hirsch AT, Criqui MH, Treat-Jacobson D, Regen- reduced to 50 mg orally twice per day when steiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treat-ment in primary care. JAMA 2001;286:1317-24.
because serum drug levels are elevated in these 3. McDermott MM, Greenland P, Liu K, Guralnik JM, patients. Common side effects of cilostazol Celic L, Criqui MH, et al. The ankle brachial index include loose stool and gastric upset.7,28,35 is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern In summary, aspirin generally is considered the antiplatelet drug of first choice. The 6th 4. Gaylis H. Diagnosis and treatment of peripheral arterial disease. JAMA 2002;287:313.
5. Merenstein JH. Diagnosis and treatment of periph- that aspirin alone (81 to 325 mg per day) or eral arterial disease. JAMA 2002;287:314.
in combination with dipyridamole, should be 6. Wilt TJ. Current strategies in the diagnosis and given indefinitely because it can modify the management of lower extremity peripheral vascu-lar disease. J Gen Intern Med 1992;7:87-101.
natural history of intermittent claudication 7. Regensteiner JG, Hiatt WR. Current medical thera- and those with high risk for future cardiovas- pies for patients with peripheral arterial disease: a cular events.39 These guidelines also suggest critical review. Am J Med 2002;112:49-57.
8. Girolami B, Bernardi E, Prins MH, Ten Cate JW, that clopidogrel may be superior to aspirin Hettiarachchi R, Prandoni P, et al. Treatment of and should be considered as an alternative intermittent claudication with physical training, treatment in these patients.39 Experimental smoking cessation, pentoxifylline, or nafronyl: a meta- analysis. Arch Intern Med 1999;159:337- or investigational agents for PAD include naftidrofuryl (Nafronyl), which is approved 9. Rigotti NA. Clinical practice. Treatment of tobacco use and dependence. N Engl J Med 2002;346:506- trol of the Hyperlipidemias (POSCH). N Engl J Med 10. A clinical practice guideline for treating tobacco 24. Pedersen TR, Kjekshus J, Pyorala K, Olsson AG, use and dependence: a U.S. Public Health Service Cook TJ, Muslinger TA, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandina- 11. Krupski WC, Nguyen HT, Jones DN, Wallace H, vian simvastatin survival study (4S). Am J Cardiol Whitehill TA, Nehler MR. Smoking cessation coun- seling: a missed opportunity for general surgery 25. Heart Protection Study Collaborative Group. MRC/ trainees. J Vasc Surg 2002;36:257-62.
BHF Heart Protection Study of cholesterol lower- 12. Fiore M. Treating tobacco use and dependence. ing with simvastatin in 20,536 high-risk individu- Rockville, Md.: U.S. Dept. of Health and Human als: a randomised placebo-controlled trial. Lancet Services, Public Health Service, 2000. (Also avail- able at http://www.surgeongeneral.gov/tobacco).
26. Graham IM, Daly LE, Refsum HM, Robinson K, 13. Beckman JA, Creager MA, Libby P. Diabetes and Brattstrom LE, Ueland PM, et al. Plasma homocys- atherosclerosis: epidemiology, pathophysiology, teine as a risk factor for vascular disease. JAMA and management. JAMA 2002;287:2570-81.
14. Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton 27. Jacques PF, Selhub J, Bostom AG, Wilson PW, AJ, Holman RR. UKPDS 59: hyperglycemia and Rosenberg IH. The effect of folic acid fortification other potentially modifiable risk factors for periph- on plasma folate and total homocysteine concen- eral vascular disease in type 2 diabetes. Diabetes trations. N Engl J Med 1999;340:1449-54.
28. Hiatt WR. Medical treatment of peripheral arterial 15. Radack K, Deck C. Beta-adrenergic blocker therapy disease and claudication. N Engl J Med 2001;344: does not worsen intermittent claudication in sub- jects with peripheral arterial disease. A meta-analy- 29. Hulley S, Furberg C, Barrett-Connor E, Cauley J, sis of randomized controlled trials. Arch Intern Med Grady D, Haskell W, et al. Noncardiovascular dis- ease outcomes during 6.8 years of hormone ther- 16. Solomon SA, Ramsay LE, Yeo WW, Parnel L, Morris- apy: Heart and Estrogen/progestin Replacement Jones W. Beta blockade and intermittent claudica- Study follow-up (HERS II). JAMA 2002;288:58-66.
tion: placebo control ed trial of atenolol and nifedip- 30. Ohta T, Sugimoto I, Takeuchi N, Hosaka M, Ishi- ine and their combination. BMJ 1991;303:1100-4.
bashi H. Indications for and limitations of exercise 17. LaRosa JC, He J, Vupputuri S. Effect of statins on training in patients with intermittent claudication. risk of coronary disease: a meta-analysis of ran- domized controlled trials. JAMA 1999;282:2340- 31. Gardner AW, Katzel LI, Sorkin JD, Goldberg AP. Effects of long-term exercise rehabilitation on 18. Ansell BJ, Watson KE, Fogelman AM. An evidence- claudication distances in patients with peripheral based assessment of NCEP Adult Treatment Panel arterial disease: a randomized controlled trial. J II guidelines. JAMA 1999;282:2051-7.
19. Elam MB, Hunninghake DB, Davis KB, Garg R, John- 32. Langbein WE, Collins EG, Orebaugh C, Maloney son C, Egan D, et al. Effect of niacin on lipid and lipo- C, Williams KJ, Littooy FN, et al. Increasing exercise protein levels and glycemic control in patients with tolerance of persons limited by claudication pain diabetes and peripheral arterial disease: the ADMIT using polestriding. J Vasc Surg 2002;35: 887-93.
study: a randomized trial. JAMA 2000;284:1263- 33. Stewart KJ, Hiatt WR, Regensteiner JG, Hirsch AT. Exercise training for claudication. N Engl J Med 20. Blankenhorn DH, Azen SP, Crawford DW, Nessim SA, Sanmarco ME, Selzer RH, et al. Effects of colestipol- 34. Leng GC, Fowler B, Ernst E. Exercise for intermit- niacin therapy on human femoral atherosclerosis. tent claudication. Cochrane Database Syst Rev 21. Buchwald H, Bourdages HR, Campos CT, Nguyen P, 35. Ouriel K. Peripheral arterial disease. Lancet 2001; Williams SE, Boen JR. Impact of cholesterol reduc- tion on peripheral arterial disease in the Program 36. A randomised, blinded, trial of clopidogrel versus on the Surgical Control of the Hyperlipidemias aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 22. Duffield RG, Lewis B, Miller NE, Jamieson CW, Brunt JN, Colchester AC. Treatment of hyperlipi- 37. De Sanctis MT, Cesarone MR, Belcaro G, Nicolaides daemia retards progression of symptomatic femo- AN, Griffin M, Incandela L, et al. Treatment of ral atherosclerosis. A randomised controlled trial. long-distance intermittent claudication with pent- oxifylline: a 12-month, randomized trial. Angiology 23. Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, et al. Effect of partial ileal bypass 38. Strandness DE Jr, Dalman RL, Panian S, Rendell surgery on mortality and morbidity from coronary MS, Comp PC, Zhang P, et al. Effect of cilostazol in heart disease in patients with hypercholesterol- patients with intermittent claudication: a random- emia. Report of the Program on the Surgical Con- ized, double-blind, placebo-controlled study. Vasc
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