1. FRAGMIN® (dalteparin sodium injection)
Prophylaxis of Ischemic Complications in Unstable Angina and Non–Q-Wave Myocardial Infarction in Combination With Aspirin Therapy
Please see full prescribing information for FRAGMIN
with the boxed warning for spinal/epidural hematomas.

2. Epidemiology and Pathophysiology
Unstable Angina and Non–Q-Wave Myocardial Infarction
Epidemiology and Pathophysiology

3. Coronary Artery Disease Leading Cause of Cardiovascular Disease
13.2 million Americans have CAD (MI or angina)
comprises >50% of all CV events in patients <75 years of age
responsible for 20% of all deaths in the US
single largest killer of American males and females
1 CAD event every 26 seconds
1 CAD death every minute
Coronary artery disease (CAD) is the leading cause of cardiovascular disease, and is responsible for 20% of all deaths in the Unites States.
13.2 million Americans have CAD, defined as either myocardial infarction or angina.
CAD is the single leading cause of mortality in the United States among both men and women.
One CAD event occurs every 26 seconds in the United States, and 1 CAD death occurs every 60 seconds.
References
Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—2006 update; a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151.
CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction.
Thom T et al. Circulation. 2006;113:e85-e151.

4. Unstable Angina and Non–Q-Wave MI Overview
ACS is a clinical syndrome referring to acute MI (Q-wave and non–Q-wave) and unstable angina
usually due to coronary artery thrombosis on atherosclerotic plaque
Unstable angina and non–Q-wave MI are a major cause of emergency medical care and hospitalization in the US
responsible for 1.4 million hospitalizations in 1996
5.3 million ER visits for evaluation of chest pain in 1997
associated with an increased risk of cardiac death
The term “acute coronary syndrome” (ACS) is used to describe patients with either acute myocardial infarction (MI) or unstable angina. The most common cause of ACS is coronary artery narrowing caused by thrombus development on preexisting atherosclerotic plaque. Both antiplatelet and anticoagulant therapies have thus become mainstays of treatment among patients with unstable angina or non–Q-wave MI.
Unstable angina and non–Q-wave MI are very common manifestations of coronary artery disease. They are associated with an increased risk of cardiac death, and are a major cause of emergency medical care and hospitalization in the United States.
In 1996 alone, 1,433,000 hospitalizations for unstable angina and non–Q-wave MI were reported.
In 1997, there were 5,315,000 visits to emergency departments for evaluation of chest pain and related symptoms.
References
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: 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). Available at:
ACS, acute coronary syndrome; LMWH, low molecular weight heparin;
MI, myocardial infarction, UH, unfractionated heparin.
Braunwald E et al Available at:

5. Non–ST-segment elevation
Acute Coronary Syndrome Evaluation Algorithm
ACS
Non–ST-segment elevation
ST-segment elevation
NSTEMI
Unstable angina MI
Patients with ischemic chest pain can be divided into those with and without ST-segment elevation, based on their electrocardiogram (ECG). Most patients with ST-segment elevation ultimately develop Q-wave acute myocardial infarction (MI) and are candidates for reperfusion therapy, although a minority develop non–Q-wave MI. Patients without ST-segment elevation are experiencing either unstable angina or non–ST-elevation MI (NSTEMI), ultimately based on the absence or presence of cardiac markers in the blood. Most patients with NSTEMI do not evolve a Q-wave on their electrocardiogram (ie, non–Q-wave MI). Patients with either unstable angina or non–Q-wave MI should receive antiplatelet therapy combined with unfractionated heparin (UH) or low molecular weight heparin (LMWH).
Patients with suspected acute coronary syndrome must be evaluated rapidly to identify signs of immediate life-threatening instability and to insure that the patient is moved rapidly to the most appropriate treatment environment and regimen.
Medical history, physical examination, ECG, and biochemical cardiac marker measurements are the basic tools for risk assessment.
References
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: 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). Available at:
Non–Q-wave MI
Q-wave MI
ACS, acute coronary syndrome; MI, myocardial infarction; NSTEMI, non–ST-elevation MI.
Adapted from Braunwald E et al Available at:

6. Unstable Angina Clinical Presentation and Classification
Diagnosis of unstable angina refers to new or worsening symptoms of myocardial ischemia:
rest angina
new-onset severe angina
increasing angina
Classification of angina:
Class I: no limitation of ordinary activity
angina only with strenuous or prolonged activity
Class II: slight limitation of ordinary activity
Class III: marked limitation of ordinary activity
Class IV: inability to carry on any physical activity without discomfort
Unstable angina is defined as new or worsening symptoms of myocardial ischemia. Classification of angina is based on the duration and intensity of symptoms.
Diagnosis of unstable angina:
Rest angina refers to angina occurring at rest, usually lasting >20 minutes.
New-onset angina refers to the development of severe angina of at least Class III (see below) in a patient without prior symptoms.
Increasing angina refers to previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (ie, worsening by at least 1 Class level to at least Class III).
Grading of angina:
Class I angina refers to the lack of symptoms with ordinary activity such as walking or climbing stairs. Angina occurs only with strenuous, rapid, or prolonged exertion.
Class II angina refers to slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly; walking uphill; walking or climbing stairs after meals, in cold, wind, or under emotional stress, or only during the few hours after awakening. Angina occurs on walking >2 blocks on the level and climbing >1 flight of stairs.
Class III angina refers to marked limitation of ordinary activity. Angina occurs on walking 1-2 blocks on the level and climbing 1 flight of stairs.
Class IV angina refers to the inability to carry on any physical activity without discomfort. Angina may be present at rest.
References
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: 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). Available at:
Braunwald E et al Available at:

7. Unstable Angina and Non–Q-Wave MI Pathogenesis
Unstable angina and non–Q-wave MI are characterized by an imbalance between myocardial O2 supply and demand, resulting in myocardial ischemia
most common cause is reduced myocardial perfusion due to a nonocclusive thrombus on a ruptured, preexisting atherosclerotic plaque
Pathogenesis and clinical presentation are similar with both conditions, differing mainly in severity
major difference is whether ischemia is severe enough to cause release of detectable quantities of markers of myocardial injury
Unstable angina and non–Q-wave myocardial infarction (MI) are characterized by an imbalance between myocardial oxygen supply and demand, resulting in myocardial ischemia. The most common cause is reduced myocardial perfusion that results from coronary artery narrowing caused by a nonocclusive thrombus that developed on a ruptured, preexisting atherosclerotic plaque.
Unstable angina and non–Q-wave MI are closely related conditions whose pathogenesis and clinical manifestations are similar but of differing severity.
At the time of presentation, patients with unstable angina and non–Q-wave MI may be indistinguishable.
Unstable angina and non–Q-wave MI differ primarily in whether the ischemia is severe enough to cause sufficient myocardial damage to release detectable quantities of markers of myocardial injury, most commonly troponin or creatine kinase-MB isoenzyme, which may be detected in the bloodstream hours after the onset of ischemic chest pain.
References
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: 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). Available at:
MI, myocardial infarction.
Braunwald E et al Available at:

8. Unstable Angina and Non–Q-Wave MI Pathogenesis (Cont’d)
Atherosclerotic plaques prone to rupture are relatively soft, with a high concentration of cholesterol esters, and have a fibrous cap
plaque rupture usually occurs where the fibrous cap is thinnest and weakest
Plaque rupture and thrombosis may lead to acute occlusion or subocclusion, resulting in unstable angina or acute MI
more frequently, an asymptomatic mural thrombus occurs, which contributes to progression of the atherosclerotic lesion
Unstable angina and non–Q-wave myocardial infarction (MI) usually result from rupture of an atherosclerotic plaque with subsequent thrombosis. Plaques prone to rupture are commonly composed of a crescentic mass of lipids (with a high concentration of cholesterol esters) separated from the vessel lumen by a fibrous cap. Rupture occurs most frequently where the cap is thinnest, most heavily infiltrated by foam cells, and therefore weakest.
Plaque rupture with subsequent thrombosis may result in acute occlusion or subocclusion with clinical manifestations of unstable angina or acute MI.
More frequently, a mural thrombus develops without clinical symptoms, and is a major contributor to the progression of the atherosclerotic lesion.
References
Théroux P, Fuster V. Acute coronary syndromes: unstable angina and non–Q-wave myocardial infarction. Circulation. 1998;97:
MI, myocardial infarction.
Théroux P et al. Circulation. 1998;97:

9. Unstable Angina and Non–Q-Wave Myocardial Infarction
The Role of Anticoagulant Agents in the Prophylaxis of Ischemic Complications

10. Hemostatic System Normal Clotting
Role of the hemostatic system:
maintain blood in a fluid state for circulation
convert blood into an insoluble gel at sites of vascular injury
Blood loss is limited following vascular injury by:
platelet adhesion and aggregation
activation of plasma coagulation proteins
The role of the hemostatic system is to balance the need to maintain blood in a fluid state so that it can circulate with the need to form a clot at sites of vascular injury.
The hemostatic system consists of 2 distinct but interlocking systems: platelets and coagulation proteins.
In the absence of vascular injury or inflammation, the healthy endothelium produces substances such as nitric oxide and prostacyclin that inhibit platelet aggregation and adhesion to the vessel wall.
When the endothelial layer is lost, plasma is exposed to the vascular subendothelium, leading to platelet adherence and activation and to activation of the plasma coagulation proteins.
References
López JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology (Am Soc Hematol Educ Program). 2004:
López JA et al. Hematology (Am Soc Hematol Educ Program). 2004:

11. Clotting Cascade Balance Between Activators and Inhibitors
Intrinsic system
XII
XIIa
XIa
Extrinsic system
(cellular injury)
Tissue factor
VII
IXa
Antithrombin
TFPI
VIIIa
Fibrinogen Xa
Prothrombin (II)
Thrombin (IIa) Va
Soluble fibrin
The clotting system is a complicated enzymatic cascade in which coagulation proteins are activated to initiate hemostasis. The process is initiated by vascular injury and results in the local formation of a fibrin clot. Precise regulation is critical in order to keep the clot from propagating beyond the site of injury. Antithrombin is an important inhibitor that maintains blood fluidity. Heparin’s ability to accelerate antithrombin activity is the basis for its anticoagulant action.1,2
The clotting cascade is initiated when vascular damage exposes tissue factor (TF) and subendothelial collagen to plasma. Tissue factor forms a complex with factor VII, which both directly and indirectly (via activation of factor IX) activates factor X. Factor X converts factor II (prothrombin) to IIa (thrombin), leading to formation of the fibrin clot.1
Blood fluidity is maintained by blood flow and by multiple inhibitors in plasma, including protein C, protein S, TF pathway inhibitor, and antithrombin.2
References
1Staton CA, Lewis CE. Angiogenesis inhibitors found within the haemostasis pathway. J Cell Mol Med. 2005;9:
2Handin RI. Bleeding and Thrombosis. In: Braunwald E et al, eds. Harrison’s Principles of Internal Medicine, 15th ed. New York, NY: McGraw-Hill Companies; 2001:
Activated
protein C
Protein C
XIIIa
Fibrin clot
Activation
Inhibition
Protein S
TFPI, tissue factor pathway inhibitor.
Adapted from Handin RI. Bleeding and Thrombosis. In: Braunwald E et al, eds. Harrison’s Principles of
Internal Medicine, 15th ed. New York, NY: McGraw-Hill Companies; 2001:

12. Unstable Angina and Non–Q-Wave MI Arterial Thrombi
Arterial thrombi are composed mainly of platelet aggregates bound together by thin fibrin strands
usually form at sites of rupture of atherosclerotic plaque
Plaque rupture exposes the subendothelium to the blood, triggering activation of platelets and the coagulation cascade
both anticoagulants and antiplatelet agents are potentially effective in reducing ischemic complications
Thrombi may form in any part of the cardiovascular system, including veins, arteries, the heart, and the microcirculation. Arterial thrombi form under conditions of high flow and are composed mainly of platelet aggregates bound together by thin fibrin strands. They usually form at sites of rupture of atherosclerotic plaque, which exposes the thrombogenic subendothelium to the blood, thereby triggering platelet activation, adherence, and aggregation as well as stimulation of the coagulation cascade. Activation of both platelets and coagulation proteins are important in the pathogenesis of arterial thrombosis.
Both anticoagulants and antiplatelet agents are therefore potentially effective in reducing the risk of ischemic complications in patients with unstable angina or non–Q-wave myocardial infarction.
References
Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;103:
MI, myocardial infarction.
Hirsh J et al. Circulation. 2001;103:

13. Anticoagulant Agents Unfractionated Heparin
Heterogeneous mixture of branched glycosaminoglycans
binds to antithrombin via a pentasaccharide
inactivates clotting factors IIa (thrombin) and Xa, and to a lesser extent, factors IXa, XIa, and XIIa
Nonspecific binding to endothelial cells, platelet factor 4, plasma proteins, macrophages, platelets, and osteoblasts
unpredictable PK/PD properties
Administered by continuous IV infusion or by SC injection 2-3 times daily
Routine coagulation monitoring required
Unfractionated heparin (UH) is a heterogeneous mixture of branched glycosaminoglycans that bind to antithrombin (AT) via a pentasaccharide, catalyzing the inactivation of thrombin and other clotting factors.
UH is heterogeneous with respect to molecular weight, anticoagulant activity, and pharmacokinetic properties. Its molecular weight ranges from 3,000-30,000 daltons, with a mean molecular weight of 15,000 daltons (approximately 45 monosaccharide units).
Clearance of UH is dependent on chain length; high molecular weight molecules are cleared faster than low molecular weight species.
UH requires a cofactor, AT, for its anticoagulant activity. UH binds to AT, producing a conformational change which converts AT from a slow thrombin inhibitor to a very rapid inhibitor.
UH binds to AT through a unique glucosamine unit contained within a pentasaccharide sequence.
AT binds covalently to thrombin (factor IIa), factor Xa, and other coagulation proteins, irreversibly inhibiting their procoagulant activity. UH then dissociates from AT and can be reutilized.
Only one third of a dose of UH binds to AT; this fraction is responsible for most of its anticoagulant effect.
UH has nonspecific binding affinities and binds to several different proteins and surfaces, including endothelial cells, platelet factor 4, plasma proteins, macrophages, platelets, and osteoblasts, leading to unpredictable pharmacokinetic and pharmacodynamic properties.
Routine monitoring of the anticoagulant effect of UH by aPTT, with appropriate dose adjustments, is required.
References
Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:188S-203S.
PD, pharmacodynamic; PK, pharmacokinetic.
Hirsh J et al. Chest. 2004;126:188S-203S.

14. Anticoagulant Agents Low Molecular Weight Heparin
Derived from UH by chemical or enzymatic depolymerization (fragments ≈ 1/3 the size of UH)
Reduced nonspecific binding to proteins and cells
predictable PK/PD properties
no need for routine coagulation monitoring
Prepared by different depolymerization methods
agents differ in PK properties
Low molecular weight heparins (LMWHs) are derived from unfractionated heparin (UH) by chemical or enzymatic depolymerization. Like UH, LMWHs produce their anticoagulant effect by activating antithrombin (AT). The development of LMWHs, however, introduced the concept that the ability of heparin molecules to inactivate thrombin are chain length-dependent. LMWHs exhibit predictable pharmacokinetic and pharmacodynamic properties, and there is no need for routine coagulation monitoring.
LMWHs are polysulfated glycosaminoglycans that are approximately one third the molecular weight of UH. They have a mean molecular weight of daltons (about 15 monosaccharide units), with a range of daltons.
Inhibition of thrombin (factor IIa) requires that heparin binds to both AT and thrombin. Heparin molecules with <18 saccharide units lose their ability to bind simultaneously to thrombin and AT, and are unable to catalyze thrombin inhibition. LMWHs therefore provide greater inhibition of factor Xa (that only requires heparin to bind to AT) than thrombin.
The depolymerization of heparin yields low-molecular-weight fragments with reduced nonspecific binding to proteins or cells. LMWHs thus have predictable pharmacokinetic and pharmacodynamic properties and a predictable dose-response relationship.
LMWHs can be administered subcutaneously, without the need for routine coagulation monitoring.
Since LMWHs are prepared by different depolymerization methods, they have different pharmacokinetic and anticoagulant profiles, and are not clinically interchangeable.
References
Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:188S-203S.
PD, pharmacodynamic; PK, pharmacokinetic; UH, unfractionated heparin.
Hirsh J et al. Chest. 2004;126:188S-203S.

15. Low Molecular Weight Heparin Mechanism of Action
Enhanced inhibition of factor Xa and thrombin by antithrombin
Preferential potentiation of factor Xa inhibition
Inhibition of factor Xa only requires LMWH to bind to antithrombin
Antithrombin
Factor Xa
LMWH
Inhibition of thrombin requires LMWH to bind to both antithrombin and thrombin
Both unfractionated heparin (UH) and low molecular weight heparins (LMWHs) enhance the inhibition of factor Xa and thrombin (factor IIa) by antithrombin (AT). LMWHs preferentially potentiate factor Xa inhibition by AT, and thus exhibit less anti-factor IIa activity relative to anti-factor Xa activity compared with UH.
The anticoagulant effect of both UH and LMWH is through their binding to AT. This produces a conformational change in AT which markedly accelerates the ability of AT to inhibit thrombin and factor Xa.
To inhibit factor Xa, heparin must only bind to AT through the high-affinity pentasaccharide, but does not need to directly bind to factor Xa.
To inhibit thrombin, heparin must bind to both AT and thrombin. Heparin molecules that contain <18 saccharide units are unable to bind thrombin and AT simultaneously. Whereas most UH chains are at least 18 saccharide units long, most LMWHs are <18 saccharide units long and therefore exhibit less inhibitory activity against thrombin than against factor Xa.
References
Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1-17.
Antithrombin
Thrombin (factor IIa)
LMWH
LMWH, low molecular weight heparin.
Adapted from Hirsh J et al. Blood. 1992;79:1-17.

16. Anticoagulant Agents Pharmacological Properties of LMWH vs UH
Reduced nonspecific binding of LMWH to proteins and cells contributes to its pharmacological properties
high bioavailability
longer plasma half-life
1:1 for UH
2:1 to 4:1 for LMWH, depending on molecular size distribution
no need for routine coagulation monitoring
reduced binding to platelets and to platelet factor 4
reduced binding to osteoblasts
Although unfractionated heparin (UH) and low molecular weight heparin (LMWH) share the same basic mechanism of action, exerting their antithrombotic effect by enhancing the inhibition of factor Xa and thrombin (factor IIa) by antithrombin, these 2 classes of agents exhibit different pharmacological properties. All of these differences can be explained by the relatively lower binding properties of LMWH.
Formation of LMWH by depolymerization of heparin yields low molecular weight fragments with reduced nonspecific binding to proteins or cells, resulting in predictable pharmacokinetic and pharmacodynamic properties. The relatively lower binding properties of LMWH contribute to:
higher bioavailability;
increased plasma half-life;
reduced ability to inhibit thrombin, resulting in a higher anti-factor Xa to anti-factor IIa ratio (1:1 for UH; 2:1 to 4:1 for LMWH, depending on the molecular size distribution of the particular LMWH);
reduced binding to platelets and to platelet factor 4;
reduced binding to osteoblasts.
Routine monitoring of the anticoagulant effect of LMWH is not necessary.
References
Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:188S-203S.
LMWH, low molecular weight heparin; UH, unfractionated heparin.
Hirsh J et al. Chest. 2004;126:188S-203S.

17. Unstable Angina and Non–Q-Wave MI ACC/AHA Practice Guidelines
For patients with unstable angina or non–Q-wave MI, antiplatelet therapy should be initiated promptly
aspirin should be administered and continued indefinitely (Class I; Level of Evidence: A)
clopidogrel should be added to aspirin in hospitalized patients in whom an early noninterventional approach is planned, and administered for at least 1 month (Class I; Level of Evidence: A)
Anticoagulation with LMWH or UH should be added to antiplatelet therapy with aspirin (Class I; Level of Evidence: A)
The American College of Cardiology/American Heart Association Practice Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction recommend a combination of antiplatelet and antithrombotic therapy in order to modify the disease process and prevent ischemic complications of death, myocardial infarction (MI), and recurrent MI.
For patients with unstable angina or non–Q-wave MI, antiplatelet therapy should be initiated promptly.
Aspirin should be administered as soon as possible after presentation and continued indefinitely (Class I [evidence and/or general agreement that a given treatment is useful and effective]; Level of Evidence: A [data were derived from multiple randomized clinical trials that involved large numbers of patients]).
Clopidogrel should be administered to hospitalized patients who are unable to take aspirin, and should be added to aspirin in hospitalized patients in whom an early noninterventional approach is planned, and administered for at least 1 month (Class I; Level of Evidence: A).
Anticoagulation with subcutaneous low molecular weight heparin or unfractionated heparin should be added to antiplatelet therapy with aspirin (Class I; Level of Evidence: A).
References
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: 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). Available at:
ACC, American College of Cardiology; AHA, American Heart Association; LMWH, low molecular weight heparin;
MI, myocardial infarction, UH, unfractionated heparin.
Braunwald E et al Available at:

18. FRAGMIN® (dalteparin sodium injection)
Use of FRAGMIN in the Prophylaxis of Ischemic Complications in Unstable Angina and Non–Q-Wave Myocardial Infarction, Concurrently Administered With Aspirin Therapy
Please see full prescribing information for FRAGMIN
with the boxed warning for spinal/epidural hematomas.

19. FRAGMIN (dalteparin sodium injection)
FRAGMIN is a LMWH produced through nitrous acid depolymerization of porcine UH
mean molecular weight = 5000 daltons
Introduced in Europe in 1985
Approved in the United States in 1994
Currently marketed in >80 countries
FRAGMIN (dalteparin sodium injection) is a low molecular weight heparin (LMWH) with antithrombotic properties, produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa, followed by a chromatographic purification process.
FRAGMIN has a mean molecular weight of 5000 daltons, with 90% of the molecules falling within the range of 2000 to 9000 daltons.
FRAGMIN was first introduced in Europe in 1985, and was approved in the United States in 1994.
FRAGMIN is currently marketed in >80 countries worldwide.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
LMWH, low molecular weight heparin; UH, unfractionated heparin.
FRAGMIN Prescribing Information, 2004.

20. FRAGMIN (dalteparin sodium injection) Pharmacological Properties
Pharmacodynamics
inhibits factor Xa in a dose-dependent manner1,2
anti-factor Xa to anti-factor IIa ratio = 2.73
produces no significant change in platelet aggregation, fibrinolysis, or clotting tests1
Pharmacokinetics
bioavailability = 87%1
time to peak plasma concentration = 4 hours1
mean terminal half-life = 3-5 hours1
elimination is predominantly via the kidneys2
FRAGMIN is a low molecular weight heparin with antithrombotic properties. FRAGMIN acts by enhancing the inhibition of factor Xa and thrombin (factor IIa) by antithrombin (AT). FRAGMIN potentiates preferentially the inhibition of factor Xa by AT.1
FRAGMIN inhibits coagulation factor Xa in human plasma in a dose-dependent manner,1,2 with a ratio of anti-factor Xa to anti-factor IIa activity of 2.7.3
FRAGMIN does not produce a significant change in platelet aggregation, fibrinolysis, or clotting tests such as prothrombin time, thrombin time, or activated partial thromboplastin time.1
After subcutaneous injection, bioavailability is 87% and peak plasma concentrations are attained after about 4 hours. Mean terminal half-life is 3-5 hours.1
Elimination takes place predominantly via the kidneys.2
References
1FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
2Dunn CJ, Jarvis B. Dalteparin: an update of its pharmacological properties and clinical efficacy in the prophylaxis and treatment of thromboembolic disease. Drugs. 2000;60:
3Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
1FRAGMIN Prescribing Information, 2004.
2Dunn CJ et al. Drugs. 2000;60:
3Weitz JI. N Engl J Med. 1997;337:

21. FRAGMIN (dalteparin sodium injection) Indications
FRAGMIN injection is indicated for the prophylaxis of ischemic complications in unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin therapy
FRAGMIN is also indicated for the prophylaxis of DVT, which may lead to PE:
in patients undergoing hip replacement surgery
in patients undergoing abdominal surgery who are at risk for thromboembolic complications
in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness
FRAGMIN injection is indicated for the prophylaxis of ischemic complications in unstable angina and non–Q-wave myocardial infarction (MI), when concurrently administered with aspirin therapy.
FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism:
in patients undergoing hip replacement surgery;
in patients undergoing abdominal surgery who are at risk for thromboembolic complications;
in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
DVT, deep vein thrombosis; PE, pulmonary embolism.
FRAGMIN Prescribing Information, 2004.

22. FRAGMIN (dalteparin sodium injection) Dosage and Administration: Unstable Angina
In patients with unstable angina or non–Q-wave MI, the recommended dose of FRAGMIN injection is 120 IU/kg of body weight, but not more than 10,000 IU SC every 12 hours with concurrent oral aspirin ( mg once daily) therapy
Treatment should be continued until the patient is clinically stabilized
The usual duration of administration is 5-8 days
Concurrent aspirin therapy is recommended except when contraindicated
In patients with unstable angina or non–Q-wave MI, the recommended dose of FRAGMIN injection is 120 IU/kg of body weight, but not more than 10,000 IU SC every 12 hours with concurrent oral aspirin ( mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5-8 days. Concurrent aspirin therapy is recommended except when contraindicated.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

23. FRAGMIN (dalteparin sodium injection) Boxed Warning
SPINAL/EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions).
SPINAL/EPIDURAL HEMATOMAS
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions).
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
FRAGMIN Prescribing Information, 2004.

24. FRAGMIN (dalteparin sodium injection) Contraindications
FRAGMIN injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive in vitro tests for anti-platelet antibody in the presence of FRAGMIN
Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non–Q-wave myocardial infarction due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for unstable angina and non–Q-wave myocardial infarction
Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN
FRAGMIN injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive in vitro tests for anti-platelet antibody in the presence of FRAGMIN.
Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non–Q-wave myocardial infarction due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for unstable angina and non–Q-wave myocardial infarction.
Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

25. FRAGMIN (dalteparin sodium injection) Warnings
FRAGMIN injection is not intended for intramuscular injection
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins
FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia
FRAGMIN injection is not intended for intramuscular injection.
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.
FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

26. FRAGMIN (dalteparin sodium injection) Precautions
FRAGMIN injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing
FRAGMIN should be used with caution in patients with bleeding diathesis, thrombocytopenia, or platelet defects, severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding
If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN should be discontinued and appropriate therapy initiated
FRAGMIN injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.
FRAGMIN should be used with caution in patients with bleeding diathesis, thrombocytopenia, or platelet defects, severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.
If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN should be discontinued and appropriate therapy initiated.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

27. FRAGMIN (dalteparin sodium injection) Additional Safety Information
The most commonly reported side effect is hematoma at the injection site
The most commonly reported side effect is hematoma at the injection site.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

28. FRAGMIN (dalteparin sodium injection) Drug Interactions
FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding
Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non–Q-wave myocardial infarction
FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding.
Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non–Q-wave myocardial infarction.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

29. FRISC Study Design Day 6 FRAGMIN 120 IU/kg bid SC Placebo bid SC
Randomization
Placebo bid SC
(n=760)
The Fragmin During Instability in Coronary Artery Disease (FRISC) trial was designed to investigate whether FRAGMIN, in addition to aspirin, is protective against new cardiac events (ischemic complications) among patients with unstable angina or non–Q-wave myocardial infarction (MI).
The FRISC study was the first and only placebo-controlled trial of a low molecular weight heparin in patients with unstable angina or non–Q-wave MI.
Eligible patients were men >40 years and women at least 1 year after menopause who were admitted to the hospital with chest pain within the previous 72 hours. All patients had to have newly developed or increased angina pectoris or angina at rest during the previous 2 months, or persistent chest pain with a suspicion of MI and at least 1 of the following electrocardiographic criteria: transient or persistent pathological ST depression of 0.1 mV, or T-wave inversion of 0.1 mV in at least 2 adjacent leads without pathological Q waves in the ischemic leads.
A total of 1506 patients were randomized to receive twice-daily subcutaneous injections with either FRAGMIN 120 IU/kg body weight (maximum 10,000 IU) or placebo for 6 days.
All patients without contraindications received aspirin 75 mg daily, β-blockers, and, as needed, calcium antagonists and organic nitrates. At the discretion of the physician, glyceryl trinitrate infusion was given at admission and at recurrence of severe or repeated episodes of angina.
The primary endpoint was the rate of death or new MI during the first 6 days.
Secondary endpoints included the frequency of revascularization procedures, the need for heparin infusion, and the combination of death, new MI, revascularization, or intravenous heparin.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Primary endpoint: Death or new MI during the first 6 days
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRISC, Fragmin During Instability in Coronary Artery Disease; MI, myocardial infarction. FRISC Study Group. Lancet. 1996;347:

30. FRISC Baseline Characteristics
FRAGMIN Placebo
Characteristic (n=746) (n=760)
Female (%) 37 35
Age, median (y) 69 70
Weight, median (kg) 75 77
BMI, median (kg/m2) 26 26
Risk factors
Current smoker (%) 20 20
Hypertension (%) 32 33
Diabetes (%) 14 13
Previous MI (%) 29 29
Heart failure (%) 11 9
Cerebrovascular disease (%) 5 5
Peripheral arterial disease (%) 4 5
Ulcer (%) 3 4
Inclusion findings
Unstable angina (%) 61 63
Non–Q-wave MI (%) 39 37
Baseline characteristics were similar across both groups in the Fragmin During Instability in Coronary Artery Disease (FRISC) trial.
Median age was 69 years in the FRAGMIN group and 70 years in the placebo group.
Approximately one third of the patients were female.
Median body mass index was 26 kg/m2 in both groups.
Cardiovascular risk factors were common in the study population, including smoking, hypertension, and diabetes. 29% of patients in both groups had a previous myocardial infarction (MI).
Approximately two thirds of patients included in the study had unstable angina and one third had non–Q-wave MI.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRISC, Fragmin During Instability in Coronary Artery Disease; BMI, body mass index; MI, myocardial infarction. FRISC Study Group. Lancet. 1996;347:

31. FRISC Baseline Characteristics (Cont’d)
FRAGMIN Placebo
Characteristic (n=746) (n=760)
Electrocardiographic changes
T-wave inversion only (%) 39 38
ST-depression only (%) 17 16
ST-depression and T-wave inversion (%) 44 46
Medications at entry
Aspirin (%) 35 37
Oral β-blockers (%) 37 38
Calcium antagonists (%) 22 23
Long-acting nitrates (%) 27 30
Number of antianginal drugs* (0/1/2) (%) 45/29/26 43/30/27
Glyceryl trinitrate infusion (%) 21 20
Diuretic (%) 23 24
Angiotensin-converting enzyme inhibitor (%) 9 8
Time between chest pain and study drug, median (h) 23 24
Baseline characteristics were similar across both groups in the Fragmin During Instability in Coronary Artery Disease (FRISC) trial.
Electrocardiographic changes are noted on the slide. Most patients had T-wave inversions, with or without ST-depression.
Aspirin, β-blockers, calcium antagonists, long-acting nitrates, and diuretics were commonly used medications at study entry. Lipid-lowering agents were very rarely used.
The median delay between the last episode of chest pain and the initiation of randomized study drug was about 24 hours.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
* β-blocker, calcium antagonist, or long-acting nitrate.
FRISC, Fragmin During Instability in Coronary Artery Disease. FRISC Study Group. Lancet. 1996;347:

32. FRISC Results FRAGMIN 120 IU/kg bid SC (n=741) Placebo bid SC (n=757)
Risk Ratio
Death or MI*
1.8%
4.8%
0.37 (P=0.001)
Death, MI, or Revascularization
2.2%
5.7%
0.38 (P<0.001)
Death, MI, Revascularization,
or IV Heparin
5.4%
10.3%
0.52 (P<0.001)
In the Fragmin During Instability in Coronary Artery Disease (FRISC) trial, FRAGMIN, given concurrently with aspirin, demonstrated a significant reduction in the primary endpoint (death or new myocardial infarction [MI]) during the first 6 days.
During the first 6 days, FRAGMIN demonstrated a significant reduction in the rate of death or new MI, compared with placebo (1.8% vs 4.8%; relative risk reduction [RRR] 63%, 95% confidence interval [CI] ; P=0.001).
FRAGMIN also significantly reduced the secondary endpoints of death, new MI, or revascularization (RRR 62%, 95% CI ; P<0.001) and death, new MI, revascularization, or intravenous heparin (RRR 48%, 95% CI ; P<0.001).
Deaths were similar in both groups (0.9% in the FRAGMIN group and 1.1% in the placebo group).
A significant reduction in new MI was observed (1.4% in the FRAGMIN group and 4.4% in the placebo group; P=0.001).
The rates of urgent revascularization (0.4% with FRAGMIN and 1.2% with placebo; P=0.07) and need for intravenous heparin (3.8% with FRAGMIN and 7.7% with placebo; P=0.001) were lower in the FRAGMIN group than in the placebo group, indicating a reduction in refractory angina.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
* Primary endpoint.
FRISC, Fragmin During Instability in Coronary Artery Disease; IV, intravenous; MI, myocardial infarction. FRISC Study Group. Lancet. 1996;347:

33. FRISC Primary Endpoint Results5 4 3 2 1
Placebo (n=759)
FRAGMIN (n=743)
(dalteparin sodium injection)
RRR 63%
(P = 0.001)
Probability
of death or MI (%)
In the Fragmin During Instability in Coronary Artery Disease (FRISC) trial, FRAGMIN, given concurrently with aspirin, demonstrated a significant reduction in the primary endpoint (death or new myocardial infarction [MI]) during the first 6 days.
During the first 6 days, FRAGMIN demonstrated a significant reduction in the rate of death or new MI, compared with placebo (1.8% vs 4.8%; relative risk reduction 63%, 95% confidence interval ; P=0.001).
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347: 1 2 3 4 5 6 7
Days
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRISC, Fragmin During Instability in Coronary Artery Disease; MI, myocardial infarction; RRR, relative risk reduction. FRISC Study Group. Lancet. 1996;347:

34. FRISC Safety FRAGMIN 120 IU/kg bid SC (n=746) Placebo bid SC (n=760)
Major Bleeding
6/746 (0.8%)
4/760 (0.5%)
Minor Bleeding
61/746 (8.2%)
2/760 (0.3%)
Thrombocytopenia
0/746
Anemia
16/746 (2%)
10/760 (1%)
During the first 6 days of the Fragmin During Instability in Coronary Artery Disease (FRISC) trial, there were very few major bleeding episodes and no differences between the 2 treatment groups.
Major bleeding was defined as a fall in hemoglobin of >2 g/dL associated with corresponding signs or symptoms, intracranial bleeding, or bleeding leading to transfusion, interruption of treatment, or death. All other bleeding was defined as minor.
Minor bleeding, mainly subcutaneous hematoma at injection sites, was more common with FRAGMIN than with placebo.
Anemia, thrombocytopenia, and other side effects were rare in both groups.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRISC, Fragmin During Instability in Coronary Artery Disease. FRISC Study Group. Lancet. 1996;347:

35. FRAGMIN (dalteparin sodium injection) Major Bleeding and Thrombocytopenia Warnings
FRAGMIN, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage; bleeding can occur at any site during therapy. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site.
In clinical trials, thrombocytopenia with platelet counts of <100,000/mm3 and <50,000/mm3 occurred in <1% and <1%, respectively. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed.
Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present.
FRAGMIN should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.
FRAGMIN, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage; bleeding can occur at any site during therapy. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site.
In clinical trials, thrombocytopenia with platelet counts of <100,000/mm3 and <50,000/mm3 occurred in <1% and <1%, respectively. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed.
Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present.
FRAGMIN should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.
References
FRAGMIN Prescribing Information, Pharmacia & Upjohn Company, Kalamazoo, MI.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRAGMIN Prescribing Information, 2004.

36. FRISC Conclusions
FRAGMIN (dalteparin sodium injection), given concurrently with aspirin, demonstrated a significant reduction in death or new MI
There were very few major bleeding episodes and no differences between the 2 groups
Treatment with a combination of FRAGMIN and aspirin for 6 days should be considered in patients with unstable angina or non–Q-wave MI
During the Fragmin During Instability in Coronary Artery Disease (FRISC) trial, FRAGMIN demonstrated a significant reduction in death or new myocardial infarction (MI) at Day 6 in patients with unstable angina or non–Q-wave MI, when given concurrently with aspirin. There was no increase in major bleeding with FRAGMIN, compared with placebo. Treatment with a combination of FRAGMIN and aspirin for 6 days should therefore be considered in patients with unstable angina or non–Q-wave MI.
References
FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRISC, Fragmin During Instability in Coronary Artery Disease; MI, myocardial infarction. FRISC Study Group. Lancet. 1996;347:

37. FRIC Study Design Acute Phase Long-term Treatment Phase
FRAGMIN (120 IU/kg bid SC)
(n=751)
FRAGMIN (7500 IU qd SC)
(n=567)
Randomization
UH*
(n=731)
Placebo (qd SC)
(n=565)
Day 6
Day 45
Primary endpoint: The primary endpoint was the composite of death, MI, or recurrent angina during the double-blind phase (Days 6-45)
The Fragmin in Unstable Coronary Artery Disease Study (FRIC) was designed to compare the efficacy and safety of FRAGMIN and unfractionated heparin (UH), when used concurrently with aspirin, in the acute management of patients with unstable angina or non–Q-wave myocardial infarction (MI), and to evaluate long-term treatment with FRAGMIN (up to 45 days).
The FRIC study was a prospective, randomized, multinational, parallel-group trial in 1482 patients with unstable angina or non–Q-wave MI, and had 2 phases.
Eligible patients were male or female patients presenting with chest pain who satisfied the clinical criteria for unstable coronary artery disease. Admission to the study had to be within 72 hours of the last episode of chest pain, and the electrocardiogram on admission had to show at least one of the following abnormalities in at least 2 adjacent leads: temporary or persistent ST-segment depression of 0.1 mV, or temporary or persistent T-wave inversion of 0.1 mV below baseline without corresponding Q waves. Patients who subsequently had biochemical evidence of non–Q-wave MI remained eligible.
Randomization for each of the 2 phases was performed once at the beginning of the study.
In the acute phase (Days 1-6), patients were randomized to either twice-daily subcutaneous (SC) FRAGMIN (120 IU/kg) or UH (dose-adjusted intravenous infusion for 48 hours, followed by 12,500 U SC twice daily).
In the double-blind prolonged treatment phase (Days 6-45), FRAGMIN 7500 IU SC once daily was compared with placebo.
Aspirin ( mg/day) was started in all patients as soon as possible after hospitalization and continued throughout the study.
The primary endpoint was the composite of death, MI, or recurrent angina during the double-blind phase (Days 6-45).
Secondary outcomes included death, MI, and recurrence of angina during the acute phase (Days 1-6), revascularization during either phase of the study, ischemia during exercise testing, and safety.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
* Dose-adjusted intravenous infusion for 48 hours, followed by 12,500 U SC bid.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; MI, myocardial infarction; UH, unfractionated heparin.
Klein W et al. Circulation. 1997;96:61-68.

38. FRIC Baseline Characteristics
FRAGMIN UH
Characteristic (n=751) (n=731)
Age, median (y) 65 65
Female (%) 37 34
Weight, median (kg) 74 73
BMI, median (kg/m2) 26 26
Inclusion criteria
Angina Class I (%) 33 30
Angina Class II (%) 13 11
Angina Class III (%) 38 42
Non–Q-wave MI (%) 16 16
Electrocardiographic changes
T-wave inversion only (%) 40 42
ST-depression only (%) 34 32
ST-depression and T-wave inversion (%) 25 25
Baseline characteristics were similar across both groups in the Fragmin in Unstable Coronary Artery Disease Study (FRIC).
Median age was 65 years in both groups.
Approximately one third of the patients were female.
Median body mass index was 26 kg/m2 in both groups.
84% of patients included in the study had unstable angina; 16% had non–Q-wave myocardial infarction.
Electrocardiographic changes are noted on the slide.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRIC, Fragmin in Unstable Coronary Artery Disease Study;
BMI, body mass index; MI, myocardial infarction; UH, unfractionated heparin. Klein W et al. Circulation. 1997;96:61-68.

39. FRIC Baseline Characteristics (Cont’d)
FRAGMIN UH
Characteristic (n=751) (n=731)
Risk factor
Current smoker (%) 25 28
Hypertension (%) 42 36
Diabetes (%) 18 18
Previous MI (%) 27 22
Heart failure (%) 9 9
Cerebrovascular disease (%) 5 6
Peripheral arterial disease (%) 8 10
Medications at entry
Aspirin (%) 57 55
β-Blocker (%) 40 34
Calcium antagonist (%) 40 37
Long-acting nitrate (%) 42 38
Diuretic (%) 18 16
Digitalis (%) 10 10
Angiotensin-converting enzyme inhibitor (%) 19 16
Baseline characteristics were similar across both groups in the Fragmin in Unstable Coronary Artery Disease Study (FRIC).
Cardiovascular risk factors were common in the study population, including smoking, hypertension, and diabetes. 27% of patients in the FRAGMIN group and 22% in the unfractionated heparin group had a previous myocardial infarction.
Aspirin, β-blockers, calcium antagonists, and long-acting nitrates were commonly used medications at study entry.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; MI, myocardial infarction; UH, unfractionated heparin. Klein W et al. Circulation. 1997;96:61-68.

40. FRIC Outcomes During the Acute Phase
FRAGMIN
120 IU/kg bid SC
(n=751)
UH*
(n=731)
Relative Risk
Death, MI, or Recurrent Angina
69 (9.3%)
55 (7.6%)
1.18 (P=0.33)
Death or MI
29 (3.9%)
26 (3.6%)
1.07 (P=0.80) MI
19 (2.6%)
23 (3.2%)
0.81 (P=0.50)
Nitrate Infusion
45 (6.0%)
39 (5.4%)
1.09 (P=0.70)
Death
11 (1.5%)
3 (0.4%)
3.37 (P=0.05)
Revascularization
36 (4.8%)
39 (5.3%)
0.88 (P=0.55)
During the acute phase (Days 1-6) of the Fragmin in Unstable Coronary Artery Disease Study (FRIC), comparable rates of the individual and combined outcomes of death, myocardial infarction (MI), or recurrence of angina were observed in the 2 treatment groups.
The composite outcome of death, MI, or recurrent angina occurred in 7.6% and 9.3% of the unfractionated heparin (UH) and FRAGMIN groups, respectively (P=NS). Death or MI occurred in 3.6% and 3.9% of the UH and FRAGMIN groups, respectively (P=NS).
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
* Dose-adjusted intravenous infusion for 48 hours, followed by 12,500 U SC bid.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; MI, myocardial infarction; UH, unfractionated heparin.
Klein W et al. Circulation. 1997;96:61-68.

41. FRIC Outcomes During the Long-Term Treatment Phase
FRAGMIN
7500 IU qd SC
(n=562)
Placebo
qd SC
(n=561)
Relative Risk
Death, MI, or Recurrent Angina
69 (12.3%)
1.01 (P=0.96)
Death or MI
24 (4.3%)
26 (4.7%)
0.92 (P=0.76) MI
17 (3.1%)
20 (3.6%)
0.92 (P=0.80)
Recurrent Angina
60 (10.8%)
57 (10.3%)
1.09 (P=0.64)
Death
11 (2.0%)
0.89 (P=0.79)
Revascularization
76 (14.3%)
76 (14.2%)
1.01 (P=0.97)
During the prolonged treatment phase (Days 6-45) of the Fragmin in Unstable Coronary Artery Disease Study (FRIC), the frequency of the combined clinical outcome of death, myocardial infarction (MI), or recurrence of angina was 12.3% in both the FRAGMIN and placebo groups.
The frequencies of the individual and combined outcomes of death, MI, or recurrent angina were similar in both groups.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; MI, myocardial infarction.
Klein W et al. Circulation. 1997;96:61-68.

42. FRIC Safety FRAGMIN UH Placebo Major Bleeding Acute Phase*
Long-Term Phase†
8/751 (1.1%)
3/567 (0.5%)
7/731 (1.0%) –
2/566 (0.4%)
Minor Bleeding
23/751 (3.1%)
28/567 (5.1%)
24/731 (3.3%)
15/566 (2.8%)
Thrombocytopenia
2/751 (0.3%)
0/567 (0%)
5/731 (0.7%)
0/566 (0%)
During the acute phase (Days 1-6) of the Fragmin in Unstable Coronary Artery Disease Study (FRIC), adverse events were rare and similar between the 2 treatment groups. Adverse events were also rare in the prolonged-treatment phase (Days 6-45); the 2 groups differed only in minor bleeding events.
Major bleeding was classified as a fall in hemoglobin of >2 g/dL, required transfusion, was intracranial, or caused death or cessation of study treatment. All other bleeding was classified as minor.
Thrombocytopenia, defined as a platelet count <100x109/L, was rare in the study.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
* Fragmin dose 120 IU/kg bid; †Fragmin dose 7500 IU qd.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; UH, unfractionated heparin.
Klein W et al. Circulation. 1997;96:61-68.

43. FRIC Conclusions
FRAGMIN (dalteparin sodium injection) is a safe and effective alternative to UH acutely in the prophylaxis of ischemic complications in patients with unstable angina or non–Q-wave MI
Prolonged therapy with FRAGMIN at a lower, once-daily dose does not confer any additional benefit over aspirin alone
FRAGMIN was not associated with an increase in major bleeding during either phase of the trial
Based on the Fragmin in Unstable Coronary Artery Disease Study (FRIC), FRAGMIN is as effective and safe as unfractionated heparin (UH), when used acutely and concurrently with aspirin, in the prophylaxis of ischemic complications in patients with unstable angina or non–Q-wave myocardial infarction, and may be an alternative to UH in this setting. Prolonged therapy with FRAGMIN at a lower, once-daily dose does not confer any additional benefit over aspirin alone. FRAGMIN was not associated with an increase in major bleeding during either phase of the trial.
References
Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
FRIC, Fragmin in Unstable Coronary Artery Disease Study; MI, myocardial infarction; UH, unfractionated heparin.
Klein W et al. Circulation. 1997;96:61-68.

44. Prophylaxis of Ischemic Complications in Unstable Angina and Non–Q-Wave MI Summary
Unstable angina and non–Q-wave MI are a major cause of emergency medical care and hospitalization in the US1
Both anticoagulants and antiplatelet agents are potentially effective in reducing ischemic complications in these patients1
FRAGMIN (dalteparin sodium injection), given concurrently with aspirin, significantly reduces death or new MI, compared with placebo,2 and is a safe and effective alternative to UH3 in the prophylaxis of ischemic complications in patients with unstable angina or non–Q-wave MI
Unstable angina and non–Q-wave myocardial infarction (MI) are common manifestations of coronary artery disease. They usually result from rupture of an atherosclerotic plaque with subsequent thrombosis, and are a major cause of emergency medical care and hospitalization in the United States. Both anticoagulants and antiplatelet agents are potentially effective in reducing the risk of ischemic complications in patients with unstable angina or non–Q-wave MI.1
FRAGMIN significantly reduces death or new MI at Day 6 in patients with unstable angina or non–Q-wave MI, when given concurrently with aspirin.2
FRAGMIN is as effective and safe as unfractionated heparin (UH), when used concurrently with aspirin, in the prophylaxis of ischemic complications in patients with unstable angina or non–Q-wave MI, and may be an alternative to UH in this setting.3
References
1Braunwald 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: 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). Available at:
2FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347:
3Klein W, Buchwald A, Hillis SE, et al, for the FRIC Investigators. 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;96:61-68.
Please see full prescribing information for FRAGMIN with the boxed warning for spinal/epidural hematomas.
MI, myocardial infarction; UH, unfractionated heparin.
1Braunwald E et al Available at:
2FRISC Study Group. Lancet. 1996;347:
3Klein W et al. Circulation. 1997;96:61-68.