在臨床上傳統肝素及低分子量肝素均能有效的預防或治療動、靜脈栓塞症。評估這類抗凝血劑使用時的安全性，發現出血為最常見且需要注意的副作用。從過去的動物實驗至臨床研究，比較使用傳統肝素或低分子量肝素出血發生率之高低，卻出現矛盾的結果。另外，國外亦有研究發現不同的國家地域，出血的發生率不同。然而，目前十分缺乏華人的在使用傳統肝素或低分子量肝素時，針對安全性評估的資料。此外，大型的臨床研究併無法真實的表現出實際臨床上，病患用藥後發生出血的危險性。
　　本研究為回溯性研究，評估使用傳統肝素或低分子量肝素時的安全性，主要包括：出血及血小板低下症，分析比較發生率、嚴重程度的型態，進而利用多重邏輯式迴歸分析評估其相關的危險因子。
　　本研究共收入425人次，其中232人次使用傳統肝素，193人次使用enoxaparin。比較病患基本特性得知，傳統肝素組多為治療急性冠心症，enoxaparin多為預防或治療靜脈血栓栓塞症及心因性血栓栓塞症。兩組分佈的族群差異很大，其中有許多會加重出血發生率的危險因子分佈不均，進而影響出血發生率之高低。
　　整體而言，本研究結果發現使用enoxaparin或傳統肝素發生出血的比率均偏高，而使用傳統肝素比enoxaparin有較高發生出血的危險性（在藥物使用期間發生任何出血的比率，傳統肝素 vs. enoxaparin：43.5% vs. 23.8%, OR: 2.791; 95% CI: 1.699-4.587, P＜0.0001）。易加重發生出血的危險因子包括：老年人、血液透析、腎功能不良、貧血、併用血栓溶解劑、tirofiban、其他抗血小板製劑、同時併用warfarin與利尿劑、接受冠狀動脈介入性治療、或接受冠狀動脈繞道手術等。其中於enoxaparin組藥物使用劑量方面，有29人次（15.0%）並未依體重之輕重來調整劑量，43人次（22.3%）並未依腎功能不良（CrCl＜30 ml/min）而調整劑量，因而導致增加出血發生的危險性。
　　本研究亦發現於使用藥物期間，傳統肝素比enoxaparin有較高發生血小板低下症的危險性（傳統肝素 vs. enoxaparin：9.9% vs. 3.1%, OR: 3.649; 95% CI: 1.313-10.141, P=0.013）。易加重發生血小板低下症的危險因子包括：肝、腎功能不良、併用利尿劑、血栓溶解劑、或接受冠狀動脈繞道手術等。至於，肝功能異常之發生率在傳統肝素組也較enoxaparin組高，而血鉀上升之發生率及臨床療效兩組則相當。

　　In clinical setting, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effectively used as preventive or curative treatment of thromboembolic diseases. The most common and concerned adverse effect of anticoagulant therapy is bleeding. LMWH is associated with lower incidence of bleeding events compared to UFH in animal studies, but there are some controversial findings about the incidence of bleeding associated with UFH or LMWH in clinical trials. Besides, the incidence of bleeding seemed to vary substantially by geographical areas. However, as far as we know, few studies have investigated the safety of UFH or LMWH in Asian. Furthermore, the incidence of bleeding events in clinical trials may not be representative of the bleeding risks in a real-world clinical setting.
　　This retrospective observational study was designed to assess the safety of UFH and LMWH in the clinical setting. Using chart review, the incidence of bleeding events and thrombocytopenia associated with UFH or LMWH were analyzed. Multivariable logistic regression analysis was used to identify independent predictors of bleeding or thrombocytopenia.
　　A total of 425 courses were enrolled which 232 courses in the UFH group and 193 courses in the enoxaparin group. In the treatment of acute coronary syndrome, UFH was more frequently prescribed than enoxaparin, while enoxaparin was more frequently used for preventive or curative treatment of venous thromboembolism and cardiogenic thromboembolism. Baseline demographic and clinical characteristics of patients between the two groups were statistically different. Thus, the incidence of bleeding events associated with UFH or enoxaparin in our study might be influenced by the uneven distribution of risk factors for bleeding.
　　Patients received UFH or enoxaparin had high rate of bleeding in our study population. The bleeding rate with UFH was higher than with enoxaparin (any bleeding during drug treatment, UFH vs. enoxaparin: 43.5% vs. 23.8%, OR: 2.791; 95% CI: 1.699-4.587, P＜0.0001). Risks factors associated with bleeding were elderly, hemodialysis, renal impairment, anemia, thrombolytic agents, tirofiban, other antiplatelet agents, warfarin and diuretic, PCI or CABG. Of dosing practices for the enoxaparin group, 29 courses (15.0%) did not recieive weight-based enoxaparin dosing. And 43 courses (22.3%) with renal impairment (CrCl＜30 ml/min) did not have enoxaparin dose adjusted. Accordingly, the inappropriate dosing of enoxaparin might increase the potential for bleeding events.
　　Besides, the UFH group had higher rate of thrombocytopenia than the enoxaparin group during drug treatment (UFH vs. enoxaparin: 9.9% vs. 3.1%, OR: 3.649; 95% CI: 1.313-10.141, P=0.013). Risks factors associated with thrombocytopenia were liver dysfunction, renal impairment, diuretics, thrombolytic agents, or CABG. In addition, the UFH group had higher rate of abnormal liver function test than the enoxaparin group. Hyperkalemia and clinical outcomes were comparable between the two groups.

第一篇 評估傳統肝素與低分子量肝素之安全性
1 Hirsh J, Warkentin TE, Shaughnessy SG et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119: 64S-94S.
2 Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.
3 Morris TA. Heparin and low molecular weight heparin: background and pharmacology. Clin Chest Med 2003; 24: 39-47.
4 Kessler CM. Current and future challenges of antithrombotic agents and anticoagulants: Strategies for reversal of hemorrhagic complications. Semin Hematol 2004; 41: 44-50.
5 Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315-28.
6 Levine MN, Raskob G, Beyth RJ et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 287S-310S.
7 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S-203S.
8 Ibbotson T, Goa KL. Enoxaparin: an update of its clinical use in the management of acute coronary syndromes. Drugs 2002; 62: 1407-30.
9 Berkowitz SD, Stinnett S, Cohen M et al. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2001; 88: 1230-4.
10 Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999; 59: 635-46.
11 林孟賢, 曾春典. 肝素(Heparin)及其在抗凝血治療的應用. 當代醫學 1995; 1: 7-14.
12 陳俊達, 陳永銘, 朱宗信. 低分子量肝素在血液透析的應用. 台灣醫學 2002; 6: 608-12.
13 Verstraete M. Heparin and thrombosis: a seventy year long story. Haemostasis 1990; 20 Suppl 1: 4-11.
14 Mannucci PM, Poller L. Venous thrombosis and anticoagulant therapy. Br J Haematol 2001; 114: 258-70.
15 de Swart CA, Nijmeyer B, Roelofs JM et al. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-8.
16 Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs and humans. Acta Med Scand 1963; 173: 619-30.
17 Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 1982; 31: 104-13.
18 謝宜璋. 急性冠心症候群之治療. 中華民國重症醫學 2003; 5: 291-6.
19 Kasper D, Braunwald E, Fauci A et al. Harrison's Principles of Internal Medicine, Harrison's Online. In, 2004 - 2005.
20 Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000; 36: 970-1062.
21 Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet 1990; 336: 827-30.
22 Theroux P, Ouimet H, McCans J et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11.
23 Oler A, Whooley MA, Oler J et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996; 276: 811-5.
24 Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002; 40: 1366-74.
25 Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002; 106: 1893-900.
26 Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998; 339: 436-43.
27 Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997; 349: 1429-35.
28 Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998; 338: 1488-97.
29 Hirsh J, Bates SM. The emerging role of low-molecular-weight heparin in cardiovascular medicine. Prog Cardiovasc Dis 2000; 42: 235-46.
30 Menon V, Berkowitz SD, Antman EM et al. New heparin dosing recommendations for patients with acute coronary syndromes. Am J Med 2001; 110: 641-50.
31 Ryan TJ, Antman EM, Brooks NH et al. 1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999; 100: 1016-30.
32 Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44: 671-719.
33 Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet 1996; 347: 561-8.
34 Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999; 20: 1553-62.
35 Klein W, Buchwald A, Hillis SE et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997; 96: 61-8.
36 Cohen M, Demers C, Gurfinkel EP et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337: 447-52.
37 Antman EM, McCabe CH, Gurfinkel EP et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999; 100: 1593-601.
38 Cohen M, Theroux P, Borzak S et al. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin. Am Heart J 2002; 144: 470-7.
39 James S, Armstrong P, Califf R et al. Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes. Eur Heart J 2002; 23: 1538-45.
40 Mukherjee D, Mahaffey KW, Moliterno DJ et al. Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network B (PARAGON B). Am Heart J 2002; 144: 995-1002.
41 Goodman SG, Fitchett D, Armstrong PW et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 2003; 107: 238-44.
42 盧澤民. 低分子量肝素在急性冠心症候群治療中的運用. 臨床醫學 2004; 2004: 129-34.
43 Mukherjee D, Topol EJ. The role of low-molecular-weight heparin in cardiovascular diseases. Prog Cardiovasc Dis 2002; 45: 139-56.
44 Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA 2003; 289: 331-42.
45 Wallentin L, Dellborg DM, Lindahl B et al. The low-molecular-weight heparin dalteparin as adjuvant therapy in acute myocardial infarction: the ASSENT PLUS study. Clin Cardiol 2001; 24: I12-4.
46 Rihn TL, Diez J. Unfractionated heparin in cardiology: redefining the standard of practice. Pharmacotherapy 2004; 24: 132S-41S.
47 Menon V, Harrington RA, Hochman JS et al. Thrombolysis and adjunctive therapy in acute myocardial infarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 549S-75S.
48 Blazing MA, de Lemos JA, White HD et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004; 292: 55-64.
49 Ferguson JJ, Califf RM, Antman EM et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004; 292: 45-54.
50 Moser LR, Kalus JS. Role of low-molecular-weight heparin in invasive management of non-ST-elevation acute coronary syndromes. Ann Pharmacother 2004; 38: 2094-104.
51 劉怡璁. 深部靜脈栓塞的治療與預防. 醫院藥學 1996; 13: 109-16.
52 陳威廷, 謝文斌. 肝素及低分子量肝素對急性肺栓塞的治療. 當代醫學 1999; 26: 1001-5.
53 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-8.
54 Cohen AT, Alikhan R. Prophylaxis of venous thromboembolism in medical patients. Curr Opin Pulm Med 2001; 7: 332-7.
55 Haas SK. Venous thromboembolic risk and its prevention in hospitalized medical patients. Semin Thromb Hemost 2002; 28: 577-84.
56 Deitelzweig S, Groce JB, 3rd. Anticoagulant prophylaxis in medical patients: an objective assessment. Pharmacotherapy 2004; 24: 120S-6S.
57 Alikhan R, Cohen AT, Combe S et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963-8.
58 Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003; 163: 759-68.
59 Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 338S-400S.
60 Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114: 561S-78S.
61 Hull RD, Raskob GE, Rosenbloom D et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322: 1260-4.
62 Goldhaber SZ. Optimizing anticoagulant therapy in the management of pulmonary embolism. Semin Thromb Hemost 1999; 25 Suppl 3: 129-33.
63 Goldhaber SZ, Elliott CG. Acute pulmonary embolism: part II: risk stratification, treatment, and prevention. Circulation 2003; 108: 2834-8.
64 Turpie AG, Levine MN, Hirsh J et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986; 315: 925-9.
65 Torholm C, Broeng L, Jorgensen PS et al. Thromboprophylaxis by low-molecular-weight heparin in elective hip surgery. A placebo controlled study. J Bone Joint Surg Br 1991; 73: 434-8.
66 Prevention of deep vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement. A randomized trial. The German Hip Arthroplasty Trial (GHAT) Group. Arch Orthop Trauma Surg 1992; 111: 110-20.
67 Hull R, Raskob G, Pineo G et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370-6.
68 Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271: 1780-5.
69 Haas S. Low molecular weight heparins in the prevention of venous thromboembolism in nonsurgical patients. Semin Thromb Hemost 1999; 25 Suppl 3: 101-5.
70 Prandoni P, Lensing AW, Buller HR et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-5.
71 Hull RD, Raskob GE, Pineo GF et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
72 Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost 2003; 29: 247-58.
73 Turpie AG, Levine MN, Hirsh J et al. Double-blind randomised trial of Org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1987; 1: 523-6.
74 Turpie AG, Gent M, Cote R et al. A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study. Ann Intern Med 1992; 117: 353-7.
75 Hillbom M, Erila T, Sotaniemi K et al. Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study. Acta Neurol Scand 2002; 106: 84-92.
76 Counsell C, Sandercock P. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischemic stroke (Cochrane review). Stroke 2002; 33: 1925-6.
77 Siragusa S, Cosmi B, Piovella F et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996; 100: 269-77.
78 Dolovich LR, Ginsberg JS, Douketis JD et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160: 181-8.
79 Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med 2004; 140: 175-83.
80 Levine M, Gent M, Hirsh J et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-81.
81 Segal JB, Bolger DT, Jenckes MW et al. Outpatient therapy with low molecular weight heparin for the treatment of venous thromboembolism: a review of efficacy, safety, and costs. Am J Med 2003; 115: 298-308.
82 Das SK, Cohen AT, Edmondson RA et al. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-6.
83 Marchetti M, Pistorio A, Barone M et al. Low-molecular-weight heparin versus warfarin for secondary prophylaxis of venous thromboembolism: a cost-effectiveness analysis. Am J Med 2001; 111: 130-9.
84 Murray RD, Deitcher SR, Shah A et al. Potential clinical efficacy and cost benefit of a transesophageal echocardiography-guided low-molecular-weight heparin (enoxaparin) approach to antithrombotic therapy in patients undergoing immediate cardioversion from atrial fibrillation. J Am Soc Echocardiogr 2001; 14: 200-8.
85 Khazan M, Scheuering S, Adamson R et al. Prescribing patterns and outcomes of enoxaparin for anticoagulation of atrial fibrillation. Pharmacotherapy 2003; 23: 651-8.
86 Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 429S-56S.
87 Clagett GP, Sobel M, Jackson MR et al. Antithrombotic therapy in peripheral arterial occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 609S-26S.
88 Koda-Kimble M, Young L, Kradjan W et al. Applied Therapeutics：The Clinical Use of Drugs. Peripheral Vascular Disorders, 7 edn., 2001.
89 Eikelboom JW, Anand SS, Malmberg K et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355: 1936-42.
90 Levine MN, Raskob G, Landefeld S et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S-21S.
91 Magee KD, Sevcik W, Moher D et al. Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes. Cochrane Database Syst Rev 2003: CD002132.
92 Thorevska N, Amoateng-Adjepong Y, Sabahi R et al. Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest 2004; 125: 856-63.
93 Macie C, Forbes L, Foster GA et al. Dosing practices and risk factors for bleeding in patients receiving enoxaparin for the treatment of an acute coronary syndrome. Chest 2004; 125: 1616-21.
94 Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980; 244: 1209-12.
95 Juergens CP, Semsarian C, Keech AC et al. Hemorrhagic complications of intravenous heparin use. Am J Cardiol 1997; 80: 150-4.
96 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S-37S.
97 Risch L, Huber AR. Improving the definition of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164: 1699.
98 楊宗泓, 鄭喻仁. 肝素誘發之血小板減少症候群. 臨床醫學 2002; 50: 404-6.
99 Shalansky SJ, Verma AK, Levine M. Factors to consider before discontinuing heparin in patients who develop thrombocytopenia. Pharmacotherapy 1999; 19: 1011-2.
100 Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-5.
101 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344: 1286-92.
102 Warkentin TE. Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management. Drug Saf 1997; 17: 325-41.
103 Messmore H, Jeske W, Wehrmacher W et al. Benefit-risk assessment of treatments for heparin-induced thrombocytopenia. Drug Saf 2003; 26: 625-41.
104 Gruel Y, Pouplard C, Nguyen P et al. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol 2003; 121: 786-92.
105 Liautard C, Nunes AM, Vial T et al. Low-molecular-weight heparins and thrombocytosis. Ann Pharmacother 2002; 36: 1351-4.
106 Edes TE, Sunderrajan EV. Heparin-induced hyperkalemia. Arch Intern Med 1985; 145: 1070-2.
107 Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575-86.
108 Wiggam MI, Beringer TR. Effect of low-molecular-weight heparin on serum concentrations of potassium. Lancet 1997; 350: 292-3.
109 Carlson MK, Gleason PP, Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparin-induced hepatotoxicity. Pharmacotherapy 2001; 21: 108-13.
110 Dukes GE, Jr., Sanders SW, Russo J, Jr. et al. Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 1984; 100: 646-50.
111 Fareed J, Jeske W, Hoppensteadt D et al. Low-molecular-weight heparins: pharmacologic profile and product differentiation. Am J Cardiol 1998; 82: 3L-10L.
112 Fareed J, Hoppensteadt D, Walenga J et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice. Clin Pharmacokinet 2003; 42: 1043-57.
113 Boneu B. An international multicentre study: Clivarin in the prevention of venous thromboembolism in patients undergoing general surgery. Report of the International Clivarin Assessment Group. Blood Coagul Fibrinolysis 1993; 4 Suppl 1: S21-2.
114 Michalis LK, Katsouras CS, Papamichael N et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am Heart J 2003; 146: 304-10.
115 Ozdemir M, Erdem G, Turkoglu S et al. Head-to-head comparison of two different low-molecular-weight heparins in acute coronary syndrome: a single center experience. Jpn Heart J 2002; 43: 433-42.
116 Cestac P, Bagheri H, Lapeyre-Mestre M et al. Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients. Drug Saf 2003; 26: 197-207.
117 Cohen M, Demers C, Gurfinkel EP et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events. Am J Cardiol 1998; 82: 19L-24L.
118 Goodman SG, Cohen M, Bigonzi F et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol 2000; 36: 693-8.
119 Malhotra S, Bhargava VK, Grover A et al. A randomized trial to compare the efficacy, safety, cost and platelet aggregation effects of enoxaparin and unfractionated heparin (the ESCAPEU trial). Int J Clin Pharmacol Ther 2001; 39: 110-5.
120 Cohen M, Gensini GF, Maritz F et al. The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial. J Am Coll Cardiol 2003; 42: 1348-56.
121 Ross AM, Molhoek P, Lundergan C et al. Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II). Circulation 2001; 104: 648-52.
122 Tatu-Chitoiu G, Teodorescu C, Fluerasu A et al. Accelerated streptokinase--a new thrombolytic regimen in acute myocardial infarction. Rom J Intern Med 1998; 36: 183-96.
123 Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358: 605-13.
124 Antman EM, Louwerenburg HW, Baars HF et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation 2002; 105: 1642-9.
125 Fox KA, Antman EM, Cohen M et al. Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-ST-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention. Am J Cardiol 2002; 90: 477-82.
126 Theroux P, Welsh RC. Meta-analysis of randomized trials comparing enoxaparin versus unfractionated heparin as adjunctive therapy to fibrinolysis in ST-elevation acute myocardial infarction. Am J Cardiol 2003; 91: 860-4.
127 Planes A, Vochelle N, Mazas F et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 1988; 60: 407-10.
128 Ament PW, Bertolino JG. Enoxaparin in the prevention of deep venous thrombosis. Am Fam Physician 1994; 50: 1763-8.
129 Kleber FX, Witt C, Vogel G et al. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614-21.
130 Simonneau G, Charbonnier B, Decousus H et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993; 153: 1541-6.
131 Merli G, Spiro TE, Olsson CG et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134: 191-202.
132 Ramzi DW, Leeper KV. DVT and pulmonary embolism: Part II. Treatment and prevention. Am Fam Physician 2004; 69: 2841-8.
133 Lacy CF, Armstrong LL, Goldman MP et al. Drug Information Handbook, 12 edn., 2004-2005.
134 Kincaid EH, Monroe ML, Saliba DL et al. Effects of preoperative enoxaparin versus unfractionated heparin on bleeding indices in patients undergoing coronary artery bypass grafting. Ann Thorac Surg 2003; 76: 124-8.
135 陳昭姿. Enoxaparin (Clexane) 具藥動學優勢的抗血栓藥. 當代醫學 1999; 26: 333-6.
136 Spinler SA, Inverso SM, Cohen M et al. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J 2003; 146: 33-41.
137 Hulot JS, Vantelon C, Urien S et al. Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Ther Drug Monit 2004; 26: 305-10.
138 Rizzieri DA, Wong WM, Gockerman JP. Thrombocytosis associated with low-molecular-weight heparin. Ann Intern Med 1996; 125: 157.
139 Collet JP, Montalescot G, Fine E et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol 2003; 41: 8-14.
140 Fong YK, Ruban P, Yeo SJ et al. Use of low molecular weight heparin for prevention of deep vein thrombosis in total knee arthroplasty--a study of its efficacy in an Asian population. Ann Acad Med Singapore 2000; 29: 439-41.
141 Yu CM, Chan TY, Tsoi WC et al. Heparin therapy in the Chinese--lower doses are required. QJM 1997; 90: 535-43.

第二篇 臨床服務
1 陳一伶, 王郁青, 李炳鈺. 外傷加護病房內執行藥事照顧之價值. 台灣臨床藥學雜誌 2003; 11: 19-31.
2 Chisholm MA, Pittman DG, Longley JM et al. Implementation of pharmaceutical care in acute medical cardiovascular patients. Hosp Pharm 1995; 30: 572-4, 7-8.
3 Leape LL, Cullen DJ, Clapp MD et al. Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. JAMA 1999; 282: 267-70.
4 Kane SL, Weber RJ, Dasta JF. The impact of critical care pharmacists on enhancing patient outcomes. Intensive Care Med 2003; 29: 691-8.
5 LaPointe NM, Jollis JG. Medication errors in hospitalized cardiovascular patients. Arch Intern Med 2003; 163: 1461-6.
6 林敏玲, 邱艷芬. 花蓮地區心臟衰竭病患對疾病認知、態度及自我照顧行為相關性之探討. 慈濟醫學 2001; 13: 57-64.
7 Rich MW, Beckham V, Wittenberg C et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995; 333: 1190-5.
8 史曉寧, 林麗嬋, 宋秀鈺. 評價衛教對老年充血性心臟衰竭知識與順從性之效果. 慈濟醫學 2000; 12: 49-57.
9 Varma S, McElnay JC, Hughes CM et al. Pharmaceutical care of patients with congestive heart failure: interventions and outcomes. Pharmacotherapy 1999; 19: 860-9.
10 Ni H, Nauman D, Burgess D et al. Factors influencing knowledge of and adherence to self-care among patients with heart failure. Arch Intern Med 1999; 159: 1613-9.
11 Cline CM, Bjorck-Linne AK, Israelsson BY et al. Non-compliance and knowledge of prescribed medication in elderly patients with heart failure. Eur J Heart Fail 1999; 1: 145-9.
12 Linne AB, Liedholm H, Israelsson B. Effects of systematic education on heart failure patients' knowledge after 6 months. A randomised, controlled trial. Eur J Heart Fail 1999; 1: 219-27.
13 Krumholz HM, Amatruda J, Smith GL et al. Randomized trial of an education and support intervention to prevent readmission of patients with heart failure. J Am Coll Cardiol 2002; 39: 83-9.
14 Pope BB. Patient-education guide. Heart failure. Nursing 2002; 32: 50-1.
15 Colonna P, Sorino M, D'Agostino C et al. Nonpharmacologic care of heart failure: counseling, dietary restriction, rehabilitation, treatment of sleep apnea, and ultrafiltration. Am J Cardiol 2003; 91: 41F-50F.
16 Lacy CF, Armstrong LL, Goldman MP et al. Drug Information Handbook, 12 edn., 2004-2005.
17 Cowie MR, Zaphiriou A. Management of chronic heart failure. BMJ 2002; 325: 422-5.
18 Cantu TG, Ellerbeck EF, Yun SW et al. Drug prescribing for patients with changing renal function. Am J Hosp Pharm 1992; 49: 2944-8.
19 胡月娟. 慢性病患者所承受的衝擊與因應行為. 護理研究 1994; 2: 140-52.
20 O'Connell MB, Johnson JF. Evaluation of medication knowledge in elderly patients. Ann Pharmacother 1992; 26: 919-21.