Introduction ⬇
AHFS Class:
Generic Name(s):
Heparin, an anionic, sulfated glycosaminoglycan anticoagulant present in mast cells, acts as a catalyst to markedly accelerate the rate at which antithrombin III (heparin cofactor) neutralizes thrombin and activated coagulation factor X (factor Xa). Unless otherwise specified in this monograph, the term “heparin” refers to unfractionated heparin, not low molecular weight heparin or both types of heparin.
Uses ⬆ ⬇
Heparin is used for prophylaxis and treatment of venous thrombosis and its extension; prophylaxis of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing major abdominal or thoracic surgery who are at risk for thromboembolism; prophylaxis and treatment of pulmonary embolism; treatment of embolization associated with atrial fibrillation or atrial flutter and/or prosthetic heart valve replacement; treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation [DIC]); and prophylaxis and treatment of peripheral arterial embolism. Heparin is also used to prevent activation of the coagulation mechanism as blood passes through an extracorporeal circuit in dialysis procedures and during arterial and cardiac surgery. In addition, the drug is used as an in vitro anticoagulant in blood transfusions. Heparin also has been used as adjunctive antithrombotic therapy in patients with unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI), or ST-segment-elevation myocardial infarction (STEMI).316,317,318,319,320,321,527,993,1100
Heparin or a low molecular weight heparin is used when a rapid anticoagulant effect is required. A coumarin anticoagulant (e.g., warfarin) is generally used for follow-up anticoagulant therapy after the effects of therapy with full-dose heparin or a low molecular weight heparin have been established and when long-term anticoagulant therapy is appropriate.1005 When warfarin is administered for follow-up treatment after full-dose heparin, therapy with warfarin and heparin should be overlapped for a short period of time.
Deep-Vein Thrombosis and Pulmonary Embolism 
Treatment
Heparin is used for the treatment of deep-vein thrombosis or pulmonary embolism. For the initial treatment of proximal deep-vein thrombosis or pulmonary embolism in adults, full-dose heparin generally is administered by continuous IV infusion;116,118,364,500,1005 alternatively, subcutaneous heparin (given initially in a weight-based dosage) may be used, with or without monitoring.116,149,1005 If warfarin is being considered for long-term anticoagulant therapy, the drug should be initiated on the same day as heparin, and such therapy should be overlapped for a minimum of 5 days and until the international normalized ratio (INR) is at least 2 for 24 hours or longer.1005
The American College of Chest Physicians (ACCP) recommends the use of heparin as an appropriate choice of anticoagulant for the initial treatment of acute proximal deep-vein thrombosis or pulmonary embolism; other options include a low molecular weight heparin or fondaparinux.1005 Among the different anticoagulant options, fondaparinux or a low molecular weight heparin generally is preferred to heparin because of more convenient administration and less risk of heparin-induced thrombocytopenia (HIT).1005 Heparin may be preferred in patients with renal impairment.1005 In addition, ACCP states that IV heparin should be considered over subcutaneous therapies in patients with pulmonary embolism in whom thrombolytic therapy is being considered or if there is a concern about the adequacy of subcutaneous absorption.1005
After full-dose heparin therapy, warfarin or a low molecular weight heparin generally is administered as follow-up anticoagulant therapy for at least 3 months in patients with venous thromboembolism.1005
Heparin also may be used for the treatment of venous thromboembolism in pediatric patients.1013 Unlike in adults, most episodes of venous thromboembolism in children are secondary to an identifiable risk factor such as the presence of a central venous access device.1013 Recommendations regarding the use of antithrombotic therapy in children generally are based on extrapolation from adult guidelines.1013 Heparin or a low molecular weight heparin is recommended by ACCP for both the initial and ongoing treatment of venous thromboembolism in children.1013 In children with central venous catheter-related thromboembolism, ACCP recommends that the catheter be removed if no longer functioning or required; at least 3-5 days of therapeutic anticoagulation is suggested prior to its removal.1013 If the central venous access device is required, ACCP suggests that anticoagulants be given until the catheter is removed.1013
Prophylaxis
General Surgery
Fixed low-dose subcutaneous heparin therapy is used for prevention of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing general (e.g., abdominal) surgery who are at risk of thromboembolism.
ACCP recommends pharmacologic (e.g., low-dose heparin) and/or nonpharmacologic/mechanical (e.g., intermittent pneumatic compression) methods of thromboprophylaxis in patients undergoing general surgery, including abdominal, GI, gynecologic, and urologic surgery, according to the patient's level of risk for thromboembolism and bleeding.1002 In general, pharmacologic prophylaxis is recommended in patients with high (and possibly moderate) risk of venous thromboembolism who do not have a high risk of bleeding, while mechanical methods are suggested in patients who require thromboprophylaxis but have a high risk of bleeding.1002 If pharmacologic thromboprophylaxis is used in patients undergoing general surgery, ACCP states that low-dose heparin or a low molecular weight heparin is preferred, but when these agents are contraindicated or not available, aspirin or fondaparinux may be considered.1002 ACCP states that the same recommendations for the use of antithrombotic agents in general surgery patients can be applied to patients undergoing bariatric surgery, vascular surgery, and plastic and reconstructive surgery.1002
Cardiac Surgery
Because the risk of venous thromboembolism in most patients undergoing cardiac surgery is considered to be moderate, mechanical methods of prophylaxis generally are recommended over pharmacologic prophylaxis in such patients.1002 However, ACCP states that use of a pharmacologic method (e.g., low-dose heparin) may be considered in cardiac surgery patients with a complicated postoperative course.1002
Thoracic Surgery
Heparin is used for the prevention of postoperative venous thromboembolism in patients undergoing major thoracic surgery.500 Pharmacologic thromboprophylaxis with low-dose heparin or a low molecular weight heparin is recommended by ACCP in patients undergoing thoracic surgery who are at high risk of venous thromboembolism, provided risk of bleeding is low.1002
Neurosurgery
Patients undergoing craniotomy, especially for malignant disease, are considered to be at high risk of venous thromboembolism.1002 Although low-dose heparin has been used for the prevention of venous thromboembolism in such patients, the benefits of pharmacologic prophylaxis may be outweighed by the possible increased risk of intracranial hemorrhage.1002 ACCP suggests the use of a mechanical method of prophylaxis (preferably intermittent pneumatic compression) in craniotomy patients; for patients considered to be at very high risk for thromboembolism, such as those undergoing craniotomy for malignant disease†, a pharmacologic method (e.g., low-dose heparin) may be added once adequate hemostasis has been established and the risk of bleeding decreases.1002
In patients undergoing spinal surgery, a mechanical method of thromboprophylaxis (preferably intermittent pneumatic compression) also is suggested, with possible addition of pharmacologic prophylaxis (e.g., heparin) in high-risk patients (e.g., those with malignancy or those undergoing surgery with a combined anterior-posterior approach) once adequate hemostasis is established and risk of bleeding decreases.1002
Trauma
In general, some form of thromboprophylaxis (with low-dose heparin, a low molecular weight heparin, or a mechanical method) is suggested by ACCP in all patients with major trauma†.1002 For major trauma patients at high risk of venous thromboembolism, including those with acute spinal cord injury, traumatic brain injury, or spinal surgery for trauma, ACCP suggests the use of both a pharmacologic and mechanical method of prophylaxis, unless contraindications exist.1002
Orthopedic Surgery
Low-dose heparin has been used for the prevention of venous thromboembolism in patients undergoing major orthopedic surgery (total hip-replacement†, total knee-replacement†, or hip-fracture surgery†).1003 ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery because of the high risk for postoperative venous thromboembolism; thromboprophylaxis should be continued for at least 10-14 days, and possibly for up to 35 days after surgery.1003 Several antithrombotic agents (e.g., low molecular weight heparins, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.1003 Although ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience, alternative agents may be considered in situations in which a low molecular weight heparin is not available or cannot be used.1003 ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered.1003
Perioperative Management of Antithrombotic Therapy
Heparin is used in the perioperative management of patients who require temporary interruption of long-term warfarin therapy for surgery or other invasive procedures.1004 Perioperative use of IV heparin or a low molecular weight heparin (bridging anticoagulation) is recommended by ACCP in some patients with venous thromboembolism, atrial fibrillation, or mechanical prosthetic heart valves depending on their risk of developing thromboembolism during temporary interruption of oral anticoagulant therapy.1004 Long-term therapy with warfarin should be resumed postoperatively when adequate hemostasis is achieved.1004
Medical Conditions Associated with Thromboembolism
Heparin has been used for the prevention of deep-vein thrombosis and pulmonary embolism in acutely ill hospitalized medical patients and in those with medical conditions associated with a high risk of thromboembolism (e.g., cancer).1001 Treatment decisions regarding the use of prophylactic anticoagulants in such patients should include an assessment of the patient's individual risk of venous thromboembolism and risk of bleeding.1001 In general, pharmacologic thromboprophylaxis is recommended only in patients who are considered to be at high risk of venous thromboembolism because the risk-to-benefit trade-off between the reduction in venous thromboembolic events and bleeding is considered to be more favorable in such patients.1001 Factors that should be considered when choosing an appropriate anticoagulant include patient preference, compliance, ease of administration, and local cost considerations.1001 ACCP recommends the use of anticoagulant thromboprophylaxis (e.g., low-dose heparin) in acutely ill, hospitalized medical patients at increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding.1001 Continued thromboprophylaxis is suggested for 6-21 days until full mobility is restored or hospital discharge, whichever comes first; extended prophylaxis beyond these periods generally is not recommended.1001 Risk of venous thromboembolism in critically ill patients in an intensive care unit (ICU) varies depending on their acute or chronic conditions (e.g., sepsis, congestive heart failure) and ICU-specific exposures and events (e.g., surgery, immobilization, mechanical ventilation, central venous catheters).1001 Low-dose heparin is suggested by ACCP as an option for pharmacologic thromboprophylaxis in critically ill patients who are not actively bleeding and do not have risk factors for bleeding.1001
Risk of venous thromboembolism is particularly high in patients with cancer.1001 Routine pharmacologic thromboprophylaxis generally is not recommended in cancer patients in the outpatient setting who have no additional risk factors for venous thromboembolism; however, ACCP suggests the use of low-dose heparin or a low molecular weight heparin for prophylaxis in cancer outpatients with solid tumors who have additional thromboembolic risk factors and are at low risk of bleeding.1001
Thromboembolism During Pregnancy
Heparin has been used for the prevention and treatment of venous thromboembolism during pregnancy.1012 Because of a more favorable safety profile, ACCP generally recommends the use of a low molecular weight heparin (rather than heparin or warfarin) for the prevention and treatment of thromboembolism during pregnancy.1012 If adjusted-dose subcutaneous heparin is used during pregnancy, ACCP states that the drug should be discontinued at least 24 hours prior to induction of labor or cesarean section to avoid an unwanted anticoagulant effect on the fetus during delivery.1012 Women at very high risk for recurrent venous thromboembolism (e.g., occurrence of proximal deep-vein thrombosis or pulmonary embolism within 2 weeks of delivery) may have therapy switched to therapeutic dosages of IV heparin, which should then be discontinued 4-6 hours prior to the expected time of delivery.1012
Prophylaxis for Other Conditions
Heparin (in therapeutic dosages), followed by warfarin, is recommended by ACCP as an option for thromboprophylaxis in children following Fontan surgery†.1013
Cardioversion of Atrial Fibrillation/Flutter
Heparin has been used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation undergoing electrical or pharmacologic cardioversion.1007 Therapeutic anticoagulation with heparin or a low molecular weight heparin may be used in patients in whom prolonged anticoagulation (e.g., with warfarin for at least 3 weeks) prior to cardioversion is not necessary or not possible; in these situations, heparin or a low molecular weight heparin generally is administered at the time of transesophageal echocardiography (TEE) or at presentation (for those with atrial fibrillation of 48 hours or less), followed by cardioversion.1007 In patients requiring urgent cardioversion because of hemodynamic instability, initiation of IV heparin or a low molecular weight heparin also is suggested, if possible; however, such therapy should not delay any emergency intervention.999,1007
In patients undergoing cardioversion for atrial flutter, experts state that the same approach to thromboprophylaxis should be used as for those with atrial fibrillation.1007
Thromboembolism Associated with Prosthetic Heart Valves
Overview
Heparin is used during conversion to maintenance therapy with warfarin to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical heart valves, including in pregnant women.293,359,996,1012 In the absence of a bleeding risk, ACCP suggests bridging anticoagulation (administration of a low molecular weight heparin in either prophylactic or therapeutic dosages or IV heparin in prophylactic dosages) during the early postoperative period after insertion of a mechanical heart valve until the patient is stable on warfarin therapy.1008 In patients with a mechanical heart valve in whom therapy with warfarin must be temporarily discontinued (e.g., those undergoing major surgery), substitution with a low molecular weight heparin or heparin is recommended in selected patients (e.g., those at high risk of thromboembolism).1004
Patients with Prosthetic Heart Valves Undergoing Surgical Procedures
In patients with a prosthetic heart valve receiving long-term oral antithrombotic therapy (e.g., warfarin) who require surgical procedures, the risk of perioperative bleeding should be weighed against the increased risk of thromboembolism that may occur as a result of discontinuance of oral antithrombotic therapy.996,1004 The American College of Cardiology (ACC) and American Heart Association (AHA) state that perioperative use of heparin should be considered for noncardiac surgery, invasive procedures, or dental procedures in patients with prosthetic heart valves who are at high risk for thrombosis without oral antithrombotic therapy; such patients include those with any mechanical mitral valve or a mechanical aortic valve with additional risk factors.996 In such high-risk patients, heparin should be initiated after discontinuance of warfarin therapy when the INR is below 2 (approximately 48 hours before surgery).996 Heparin should be discontinued 4-6 hours before the procedure and then reinitiated as early as possible after surgery once hemostasis has been established.996 Therapy with heparin should then be continued until the patient has achieved therapeutic anticoagulation on warfarin therapy (as assessed by the INR).996
Pregnant Women with Prosthetic Heart Valves
Heparin has been used for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves.†996,1012,1143
The risk of valve thrombosis in pregnant women with prosthetic mechanical heart valves is lowest with the use of warfarin.359,996,1012 However, warfarin crosses the placenta and is associated with adverse embryopathic and fetopathic effects, prematurity, stillbirths, and spontaneous abortions, with the risk of embryopathy being highest during weeks 6-12 of gestation.293,359,996,1012 Heparin does not cross the placenta and is considered safer to the fetus than warfarin; however, use of heparin has been associated with an increased maternal risk for valve thrombosis, death, and major bleeding complications.293,359,996,1012 In addition, thrombosis of prosthetic heart valves, resulting in maternal and/or fetal death in some cases, has occurred in some pregnant women receiving prophylaxis with a low molecular weight heparin (enoxaparin).417,424,425,426,427,428,429,430,431,432,1012
The American College of Cardiology/American Heart Association (ACC/AHA) issued guidelines for the management of patients with valvular heart disease, which includes recommendations for the management of women with mechanical heart valves who are pregnant or plan to become pregnant.1143 Multiple strategies are recommended to reduce, as well as balance, the maternal (e.g., valve thrombosis, death) and fetal risks (e.g., fetal loss, teratogenicity).1143 No single anticoagulation strategy is optimally safe for both the mother and the fetus; maternal and fetal risks can be reduced, but not eliminated.1143 Options include warfarin continuation throughout pregnancy, dose-adjusted heparin or low molecular weight heparin with frequent anti-Xa level monitoring throughout pregnancy, or sequential therapy with dose-adjusted heparin or with frequent anti-Xa level monitoring during the first trimester and warfarin during the second and third trimesters.1143
Arterial Thromboembolism
Full-dose heparin therapy has been used to reduce the extent of ischemic injury in patients with acute arterial emboli or thrombosis; however, ACCP states that formal studies demonstrating improved outcomes have not been conducted.500,1011 In patients with limb ischemia secondary to arterial emboli or thrombosis, immediate systemic anticoagulation with heparin to prevent thrombotic propagation is suggested by ACCP.1011
For neonates and children requiring cardiac catheterization via an artery, thromboprophylaxis with IV heparin is recommended.1013 If femoral artery thrombosis occurs following cardiac catheterization, initial treatment with therapeutic-dose IV heparin is recommended, followed by subsequent conversion to a low molecular weight heparin or continued treatment with heparin to complete 5-7 days of therapeutic anticoagulation.1013
Disseminated Intravascular Coagulation
Heparin is used for the diagnosis and treatment of acute and chronic consumptive coagulopathies, including DIC.500 The use of heparin in patients with DIC is controversial. Generally, the underlying cause of the DIC episode should be determined and corrected. However, if the underlying cause is not evident or cannot readily be corrected, some clinicians recommend the use of heparin. Heparin appears to be most effective in the treatment of DIC when gross thrombosis or purpura fulminans is present; however, the drug appears to have little effect on the overall mortality associated with acute DIC.
Thrombosis Associated with Indwelling Venous or Arterial Devices
Heparin lock flush solution is used to maintain patency of indwelling peripheral or central venipuncture devices designed for intermittent injections and/or blood sampling;112,214,215,216,217,218,219,221,222,223,224,225,232,233,234 the flush solution should not be used for anticoagulant therapy. Although such flush solutions generally contain low concentrations of heparin sodium (e.g., 10 or 100 units/mL) in 0.9% sodium chloride injection or other IV fluid, the optimum concentration of heparin sodium, and whether the drug is even needed in all circumstances, for maintaining patency of indwelling venipuncture devices have not been established.112,214,215,216,217,218,219,221,222,223,224,225,232,233,270 Since the optimum concentration of heparin sodium for maintaining patency in indwelling venipuncture devices has not been established,112,215,217,218,219,232,238 use of the lowest concentration shown to be effective (e.g., 10 units/mL) has been suggested when such heparin-containing flush solutions are deemed necessary.215,219,238 Heparin has no fibrinolytic activity and will not lyse existing clots; therefore, thrombolytic agents (e.g., urokinase [no longer commercially available in the US]) rather than heparin would be appropriate for catheters with preexisting obstruction with blood or fibrin.234,236,237
Evidence principally in adults112,216,221,222,224,225,233,271 and to a limited extent in children,223 including pooled analysis of data from various studies,225,242 indicates that heparin-containing solutions are no more effective than 0.9% sodium chloride injection alone for maintaining patency of venipuncture devices in peripheral veins when blood is not aspirated into the device , and some clinicians state that routine use of heparin-containing flush solutions may not be advisable because of heparin-associated drug-drug incompatibilities, laboratory test interferences, and rare but potentially serious adverse effects.112,214,215,216,221,223,225,226,228,229,230,233,235,238,243,244 It also has been suggested that the type of solution used to maintain venipuncture device patency may not be as important as the positive pressure maintained in the IV line by the capped (sealed) injection device, which appears to prevent blood reflux and clot formation in the device.224,225,238 In several randomized, double-blind studies in which peripherally placed venipuncture devices composed of fluoroethylene propylene (FEP-Teflon®) principally were used,112,216,221,223 use of 0.9% sodium chloride injection for flushing indwelling venipuncture devices was associated with patency rates similar to those achieved with flush solutions containing 10 or 100 units/mL of heparin sodium, and the frequency of phlebitis with the use of these solutions also was similar.112,214,215,216,221,222,223,224,225 Therefore, some clinicians state that the use of 0.9% sodium chloride injection alone is sufficient to maintain patency of venipuncture devices, at least those made of FEP-Teflon®215 when such devices are placed in peripheral veins and used for intermittent IV access.215,219,221,223,224,233,238 Limited data in children also suggest no difference between 0.9% sodium chloride injection alone or with heparin sodium 10 units/mL in maintaining peripheral IV catheter patency,223 although additional controlled studies in larger numbers of patients are needed to evaluate more fully the potential risks and benefits of using heparinized versus non-heparinized flush solutions routinely for peripheral venipuncture devices in children and infants.223,225,238,241
There is some evidence suggesting that heparin-containing flush solutions are more effective than 0.9% sodium chloride injection alone in maintaining patency of indwelling venipuncture devices used to obtain blood specimens 214,215,219 and of catheters used for arterial access (arterial lines).239,240 Therefore, pending further study,242 it has been suggested that flush solutions containing heparin be used for maintaining catheter patency in these situations.215,239
For primary thromboprophylaxis of central venous access devices in children, ACCP states that intermittent or continuous infusions of heparin or 0.9% sodium chloride injection generally are used.1013
Neonates and children with peripheral arterial catheters should receive thromboprophylaxis with continuous infusions of low concentrations of heparin.1013 If arterial thrombosis of the catheter occurs, ACCP suggests immediate removal of the catheter; anticoagulant therapy with heparin may be considered as an option for the treatment of symptomatic catheter-related thromboembolism.1013 ACCP also suggests that neonates with umbilical arterial catheters receive thromboprophylaxis with low-dose heparin infusion through the catheter to maintain patency.1013
Acute Ischemic Complications of ST-Segment Elevation Myocardial Infarction
Heparin is used as adjunctive therapy in the management of acute ST-segment-elevation MI (STEMI).527 The current standard of care in patients with STEMI is timely reperfusion (with primary percutaneous coronary intervention [PCI] or thrombolytic therapy).527,994 Adjunctive therapy with anticoagulant (e.g., heparin) and antiplatelet (e.g., aspirin and clopidogrel) agents should be used during and after successful coronary artery reperfusion for the prevention of early reocclusion and death.162,165,166,167,168,169,170,171,172,173,174,175,527 The American College of Cardiology Foundation (ACCF) and AHA state that patients with STEMI undergoing thrombolytic therapy should receive an anticoagulant (e.g., heparin, enoxaparin, fondaparinux) for a minimum of 48 hours, and preferably for the duration of the index hospitalization, up to 8 days or until revascularization is performed.527 Enoxaparin is preferred over heparin if extended anticoagulation is necessary beyond 48 hours.527 Heparin also is used for anticoagulation therapy during PCI.527
Combined analysis of results from 3 large, randomized comparative studies in patients with suspected acute MI who received thrombolytic therapy (i.e., anistreplase [no longer commercially available in the US], recombinant tissue-type plasminogen activator [rt-PA], or streptokinase [no longer commercially available in the US]) plus low-dose aspirin with or without subcutaneous heparin sodium (12,500 units initiated approximately 4 or 12 hours after thrombolytic therapy and usually continued for 1 week or until hospital discharge) indicated that adjunctive therapy with heparin reduced early (i.e., during heparin treatment) reinfarction and death; however, mortality at long-term follow-up (e.g., at 7 weeks or 6 months) was not different in these studies, and the addition of heparin was associated with an increased risk of bleeding, including cerebral hemorrhage.202,203,204,205 It should be noted that therapy with heparin in most patients in these studies was not given IV nor was it initiated as early in the course of treatment as was the case in most other studies in which mortality with rt-PA (e.g., alteplase) therapy was examined.168,204,206,207,208,209,210
Current evidence from studies in which IV heparin has been administered simultaneously with thrombolytic therapy,272,277,278,279 including results of a multicenter study in more than 41,000 patients with acute MI (GUSTO-1),272 suggests that conjunctive therapy with IV heparin, in addition to aspirin, is effective in reducing reocclusion following thrombolytic therapy for acute MI.275 In addition, results of a pooled analysis of data from 300 studies of thrombolytic treatment for acute MI indicated a reduction in mortality for thrombolytic regimens including rt-PA but not for those including streptokinase (no longer commercially available in the US) or anistreplase (no longer commercially available in the US) when regimens in which early conjunctive heparin (initiated before or with thrombolytic agents) was used were compared with those in which late therapy with heparin (initiated after termination of thrombolytic therapy) was used;276 these data are consistent with results of the GUSTO-1 study demonstrating a mortality benefit for IV alteplase plus simultaneous IV heparin compared with streptokinase-heparin regimens.272,273,274 However, some evidence suggests a narrow margin of safety for upward adjustment of heparin dosage, and the need for serial monitoring of aPTT, in patients receiving heparin concurrently with thrombolytic therapy for acute MI.281,282 In 2 multicenter, randomized studies designed to compare IV heparin with IV hirudin (an antithrombin inhibitor) as early (within 1 hour following thrombolysis) adjunctive therapy to thrombolytic agents (rt-PA or streptokinase) and aspirin in patients with acute MI, administration of IV heparin in weight-adjusted dosages approximately 20% higher than the dosages used in the GUSTO-1 study was associated with a marked increase in the risk of hemorrhagic stroke, and recruitment of patients into the studies was halted prematurely.281,282 In addition, major hemorrhage appeared to be associated with prolonged aPTT values (i.e., those above the target aPTT range of 60-90 seconds [generally 2-3 times the control value]), especially during the first 12 hours following thrombolysis.281,282
Acute Ischemic Complications of Percutaneous Coronary Intervention
Heparin also is used to reduce the risk of ischemic complications in patients undergoing PCI.380,994 Adjunctive therapy with heparin is recommended in addition to aspirin, a GP IIb/IIIa-receptor inhibitor (i.e., abciximab, eptifibatide) and/or a P2Y12 receptor-antagonist (e.g., clopidogrel) for patients undergoing such procedures.380,455,994 Use of a parenteral anticoagulant is recommended in patients undergoing PCI to prevent thrombus formation at the site of arterial injury, the coronary guidewire, and in the catheters used for the procedure.994 IV heparin is recommended by the ACCF, AHA, and the Society for Cardiovascular Angiography and Interventions (SCAI) as an appropriate choice of anticoagulant for use during PCI.994 The activated clotting time (ACT) generally has been used to assess the degree of heparin anticoagulation in patients undergoing PCI; however, the utility of ACT monitoring recently has been questioned because a clear relationship between ACT values and clinical outcomes has not been demonstrated.994
Heparin used in conjunction with GP IIb/IIIa-receptor inhibitors has further reduced the incidence of ischemic complications of PCI compared with heparin alone.385,994 Since GP IIb/IIIa-receptor inhibitors may have additive effects on ACT in patients receiving one of these drugs with heparin, the dosage of heparin required to maintain an appropriate ACT during such concurrent therapy may be lower than with heparin monotherapy.380,994 Full-dose anticoagulation is no longer used after successful PCI procedures.994 In most cases, the femoral sheath is removed when the ACT falls to less than 150-180 seconds or when the aPTT decreases to less than 50 seconds.994
Results of clinical trials indicate that direct thrombin inhibitors (e.g., argatroban) are at least as effective as heparin in reducing the risk of acute ischemic complications (e.g., death, MI, need for urgent revascularization procedures) in patients undergoing PCI.994,1006 For patients with HIT or a history of HIT undergoing urgent PCI, ACCF, AHA, and ACCP state that bivalirudin or argatroban may be used in place of heparin.994,1006
Cardiac and Arterial Vascular Surgery
Heparin is used for the prevention of blood clotting in arterial and cardiac surgery.500,1006
During cardiac surgery, heparin is commonly used to prevent coagulation in the cardiopulmonary bypass circuit and in the operative field.500,1006 ACCP states that a nonheparin anticoagulant (e.g., bivalirudin) may be used in place of heparin in patients with acute HIT or subacute HIT (platelets have recovered, but HIT antibodies are still present) who require urgent cardiac surgery.1006 Because HIT antibodies are transient, patients with a history of HIT may be re-exposed to heparin in special circumstances.1006 ACCP states that short-term use of heparin may be appropriate in patients with a remote (more than 3 months) history of HIT and no detectable antibodies who require cardiac surgery.1006
Acute Ischemic Complications of Non-ST-Segment-Elevation Acute Coronary Syndromes
Heparin is used in the management of non-ST-segment-elevation acute coronary syndromes (NSTE ACS)†.992,993,994,1010,1100 Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.805,1100 The AHA/ACC guideline for the management of patients with NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as PCI with coronary artery stent implantation or coronary artery bypass grafting [CABG]) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-adrenergic blocking agent (β-blocker), antiplatelet agents, anticoagulant agents, nitrates, and analgesic agents regardless of the initial management approach.1100
All patients with NSTE ACS should receive immediate antiplatelet therapy (e.g., aspirin, clopidogrel) unless contraindicated or not tolerated.992,993,994,1010,1100 An anticoagulant agent should be added to antiplatelet therapy as soon as possible after presentation.993 Initial parenteral anticoagulants with established efficacy in patients with NSTE ACS include enoxaparin, heparin, bivalirudin (only in patients who are being managed with an early invasive strategy), and fondaparinux.993,1100 Fondaparinux is preferred over heparin therapy in patients with an increased risk of bleeding.993 Heparin anticoagulation should be continued for 48 hours or until PCI is performed.1100 In patients who will undergo CABG and who are already receiving heparin, the drug should be continued during surgery.993 Patients receiving other anticoagulants (enoxaparin, fondaparinux, or bivalirudin) in whom CABG is to be performed should discontinue the anticoagulant and initiate heparin during the surgery.993
In patients in whom conservative medical therapy is selected as a postangiographic management strategy, recommendations for continued antiplatelet and anticoagulant therapy generally are based on the presence of coronary artery disease.993 ACC, AHA, and ACCF state that the optimum duration of heparin therapy has not been established; in clinical trials, the drug generally was administered for 2-5 days.993
Current evidence indicates that heparin given by continuous IV infusion can reduce the incidence of acute MI, death, and recurrent refractory angina pectoris in patients with NSTE ACS†.256,257,258,259,260,263,264,265,266,269
Early initiation of therapy with IV heparin appears to be necessary for beneficial effects in patients with unstable angina since initiation of the drug more than 24 hours following onset of symptoms has failed to reduce the incidence of adverse coronary events (e.g., angina, MI).261,262,267,268 In clinical studies in patients with acute unstable angina, data suggest that continuous IV infusion of heparin is more effective than intermittent IV administration, possibly because of inadequate anticoagulation achieved with the latter method.257,260,262,267,268
Cerebral Thromboembolism
Although therapeutic-dose anticoagulation has been used in patients with acute ischemic stroke, there is strong evidence that such treatment is associated with worse outcomes than aspirin therapy in terms of increased mortality and rates of nonfatal major extracranial bleeding.1009 Therefore, ACCP recommends early treatment (within 48 hours) with aspirin over therapeutic anticoagulation to prevent recurrent cerebral thromboembolism in patients with acute ischemic stroke or transient ischemic attacks (TIA).1009 However, heparin anticoagulants (i.e., low molecular weight heparins or heparin) may be used in prophylactic dosages for thromboprophylaxis in some patients with acute ischemic stroke; those with additional risk factors for venous thromboembolism are more likely to benefit from such therapy.1009 ACCP suggests that thromboprophylaxis with a low molecular weight heparin (in prophylactic dosages), subcutaneous heparin, or an intermittent pneumatic compression device be used in patients with acute ischemic stroke and restricted mobility.1009 Among the anticoagulant options, ACCP suggests the use of a low molecular weight heparin over heparin.1009 Prophylactic-dose heparin or a low molecular weight heparin usually is initiated within 48 hours of the onset of stroke and is continued throughout the hospital stay until the patient regains mobility; such heparin therapy should not be given within the first 24 hours after administration of thrombolytic therapy.1009
Heparin is recommended by ACCP as an option for the initial treatment of acute arterial ischemic stroke in children† until dissection and embolic causes have been excluded.1013 When dissection or cardioembolic causes have been excluded, daily aspirin therapy (in prophylactic dosages) is suggested for a minimum of 2 years.1013 In children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy†, ACCP recommends ongoing antithrombotic therapy (e.g., with heparin) for 3 months.1013 In neonates, antithrombotic therapy generally is not recommended for a first occurrence of arterial ischemic stroke in the absence of a cardioembolic origin; however, ACCP states that heparin may be considered in neonates with a first episode of arterial ischemic stroke associated with a documented cardioembolic source.1013
Heparin or a low molecular weight heparin is suggested for the treatment of acute cerebral venous sinus thrombosis† in adults.1009 Heparin or a low molecular weight heparin also is recommended for the initial treatment of cerebral venous sinus thrombosis without substantial intracranial hemorrhage in children†, followed by continued treatment with a low molecular weight heparin or warfarin for at least 3 months; another 3 months of anticoagulation is suggested if symptoms persist or there is continued occlusion of the cerebral venous sinuses.1013 Although the evidence is not as compelling as for children without substantial hemorrhage, ACCP also suggests that anticoagulation may be used for the treatment of cerebral venous sinus thrombosis in children with substantial hemorrhage.1013
Renal Vein Thrombosis
Renal vein thrombosis† is the most common cause of spontaneous venous thromboembolism in neonates.1013 Although use of anticoagulant therapy for this condition remains controversial, heparin is suggested by ACCP as a possible treatment option for neonates with renal vein thrombosis.1013
Complications of Pregnancy
Heparin should be used during pregnancy† only when clearly needed, weighing carefully the potential benefits versus the possible risks to the mother (e.g., bleeding, osteopenia/osteoporosis) and fetus (e.g., bleeding at the uteroplacental junction [heparin does not cross the placenta], complications secondary to maternal bleeding).290,292,294,295,1012 Heparin has been used in combination with aspirin for the prevention of complications of pregnancy† (e.g., pregnancy loss in women with a history of antiphospholipid syndrome and recurrent fetal loss).290,293,294,295,296,297,298,299,300,315 The presence of maternal antiphospholipid antibodies is associated with an increased risk of thrombosis and pregnancy loss.290,295,315,1012 Data from several small comparative studies indicate that combined prophylaxis with heparin and low-dose aspirin is more effective than aspirin alone or aspirin combined with a corticosteroid in preventing recurrent pregnancy loss (fetal death, miscarriage), preeclampsia, or premature delivery in women with antiphospholipid syndrome (Hughes syndrome).290,295,296,297,298,299,300,301,315 A systematic review in more than 800 pregnant women with antiphospholipid antibodies and a history of fetal loss supports the finding that combined prophylaxis with heparin and aspirin is superior to aspirin alone in reducing incidence of pregnancy loss.1012 The beneficial effect of such prophylactic therapy may result from aspirin-induced suppression of thromboxane A2-mediated vasospasm, ischemia, and thrombosis in the placental vasculature297,298,299,302,303,304,305,306,307,308,309,310,315 and by heparin-induced anticoagulation combined with binding to phospholipid antibodies that protects the trophoblast from antibody attack and thus promotes successful implantation in early pregnancy.299
ACCP recommends that women with antiphospholipid antibody (APLA) syndrome in whom recurrent (3 or more) pregnancy loss has occurred should receive antepartum prophylactic or intermediate dosages of subcutaneous heparin in conjunction with low-dose aspirin.290,295,299,300,315,1012 Alternatively, therapy with a low molecular weight heparin instead of heparin may be considered.1012
Because of experience in women with antiphospholipid syndrome, heparin and aspirin (often combined with immune globulin) also have been used to prevent venous thromboembolism and early pregnancy loss in women who have undergone in vitro fertilization†.294,311,312,313,314 1012 However, current evidence suggests that the overall absolute risk of symptomatic thrombosis appears to be low in women undergoing in vitro fertilization.1012 Therefore, ACCP recommends against routine thromboprophylaxis in most women undergoing assisted reproduction.1012
Anticoagulation in Blood Transfusions, Blood Samples, and Other Procedures
Heparin is used as an in vitro anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures.373,500
Dosage and Administration ⬆ ⬇
Administration
USP has changed its labeling standard for Heparin Sodium Injection, USP and Heparin Lock Flush Solution, USP to require that carton and container labels for these products clearly state the strength of the entire container (amount of heparin per total volume of container), followed in close proximity by the strength per mL in parentheses. 501The labeling change eliminates the need to calculate the total amount of heparin in a product containing more than 1 mL and thus reduces the chance of a dosing error. 501The new labeling standard for heparin was effective as of May 1, 2013. 501Clinicians should check the label on all heparin products to confirm the correct formulation and strength prior to dispensing and administering the drug. 373,500,501
For full-dose therapy, heparin is administered by IV infusion, intermittent IV injection, or deep subcutaneous (intrafat) injection. For fixed low-dose therapy, heparin usually is administered by deep subcutaneous injection. Heparin should not be administered IM because of the frequency of irritation, pain, and hematoma at the injection site .
IV Administration
Heparin lock flush solution is not intended for systemic anticoagulation.462,464 Conversely, heparin injection should not be used as a catheter lock flush solution.373,500
For full-dose therapy, many clinicians advocate continuous IV infusion of heparin rather than intermittent IV injection because of a more constant degree of anticoagulation and a lower incidence of bleeding complications. To avoid fluctuations in the rate of administration and minimize the risk of overdosage, IV infusions of full doses of heparin should be administered with a constant-rate infusion pump if possible.
Heparin solutions for IV infusion may be prepared by diluting the drug in a compatible IV solution; when heparin is added to an IV solution, it is recommended that the container be inverted at least 6 times to ensure adequate mixing and prevent pooling of the drug in the solution. Alternatively, commercially available solutions of heparin in 0.45 or 0.9% sodium chloride injection or in 5% dextrose injection may be used. When one of the commercially available IV infusion solutions of heparin is used, accompanying labeling should be consulted for proper methods of administration and associated precautions.
Intermittent IV injections of heparin may be given undiluted or diluted with 50-100 mL of 0.9% sodium chloride injection.
Heparin injections and solutions for infusion and heparin lock flush solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; the injection or solution should not be used if it is discolored, unclear, or contains a precipitate.373,500 However, slight discoloration does not alter potency.500
Standardize 4 Safety
Standardized concentrations for heparin have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 1101,1102Multidisciplinary expert panels were convened to determine recommended standard concentrations. 1101,1102Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 1101,1102 For additional information on S4S (including updates that may be available), see [Web].
Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Heparin1101 1102
Patient Population | Concentration Standards | Dosing Units |
|---|
Adults | 100 units/mL | units/hour or units/kg/houra |
Pediatric patients (<50 kg) | 50 units/mL or 100 units/mL for anticoagulant therapy | units/kg/hour |
| 2 units/mL for arterial line maintenance | |
aThe S4S panel recommends trying to standardize dosing units but understands that some protocols may use “flat” dosing while others may require weight-based dosing
Subcutaneous Administration
Deep subcutaneous injections of heparin should be made with a 25- or 26-gauge ½- or (5/8)-inch needle above the iliac crest or into the abdominal fat layer to minimize tissue trauma; abdominal injections should not be made within 2 inches of the umbilicus. The tissue around the injection site should be grasped creating a tissue roll and the needle inserted quickly into the elevated tissue perpendicular to the skin surface. Finger pressure on the tissue roll should be reduced slightly and the solution fully injected. The needle should be rapidly withdrawn while simultaneously releasing the tissue roll and gentle pressure should be applied to the area for 5-10 seconds. Injection sites should not be massaged before or after injection, and sites should be changed for each dose to prevent the development of a massive hematoma. It has been recommended that the plunger of the syringe not be pulled back to see if a vessel has been entered; however, most clinicians state that although it is not necessary, there is no reason why aspiration cannot be performed to determine if a blood vessel has been entered prior to injection of the solution.
Laboratory Monitoring of Therapy
The activated partial thromboplastin time (aPTT) is the most commonly used laboratory method for monitoring full-dose heparin therapy. The activated coagulation time (ACT) may also be used and is especially convenient for monitoring the degree of anticoagulation in patients undergoing extracorporeal circulation because the test can be performed at bedside. Although the whole blood clotting time (Lee-White clotting time) was used in the past to monitor full-dose heparin therapy, the test is rarely used now because it is less convenient and less reproducible than are other available coagulation tests. The generally accepted therapeutic range for the aPTT during full-dose IV or subcutaneous heparin therapy is 1.5-2 times the control value in seconds, and the generally accepted therapeutic range for the ACT is 2.5-3 times the control value in seconds.500 However, in some patients at high risk for thromboembolic events (e.g., pregnant women with mechanical heart valves) an aPTT of at least 2 times the control value has been used.359,996 When full-dose heparin therapy is administered by continuous IV infusion, coagulation tests should be performed prior to initiation of therapy, approximately every 4 hours during the early stages of therapy, and daily thereafter.500 When full-dose heparin therapy is administered by intermittent IV injection or deep subcutaneous injection, coagulation tests should be performed prior to each dose (or 4-6 hours following the dose for deep subcutaneous injection) during the early stages of therapy, and at appropriate intervals thereafter.500 Laboratory monitoring of coagulation tests is not usually performed when fixed low-dose subcutaneous heparin therapy is used because currently available coagulation tests are generally unaffected or only minimally prolonged. Regardless of the route of administration, it is recommended that platelet counts and hematocrit be monitored and tests for occult blood in the stool be performed periodically during the entire course of heparin therapy.
Dosage
Dosage of heparin sodium is expressed in USP units. USP units and international units (IU, units) for heparin sodium are equivalent.489,490
Dosage requirements for full-dose heparin sodium therapy vary greatly among individual patients, and dosage should be carefully individualized based on clinical and laboratory findings in order to obtain optimum therapeutic effects without incurring hemorrhage. (See Laboratory Monitoring of Therapy under Dosage and Administration: Administration.) Because of a lack of adequate and well-controlled studies of heparin in pediatric patients, dosage recommendations in this population generally are based on clinical experience.373,500 Geriatric patients (older than 60 years of age) may require a lower dosage of heparin sodium.373,500 (See Cautions: Geriatric Precautions.)
The optimum duration of heparin therapy for thrombotic disorders has not been definitely established and must be determined by the condition being treated and its severity. Full-dose heparin is generally continued for at least 5 days in patients with acute venous thrombosis or pulmonary embolism, and for 2 days in patients with myocardial infarction (MI)†.527,993 1005 A coumarin anticoagulant (e.g., warfarin) generally is administered for follow-up treatment after full-dose heparin, and therapy with the 2 drugs is usually overlapped for 4-5 days until an adequate response to the coumarin derivative is obtained (e.g., as indicated by INR values exceeding 2 on two consecutive days).451 (See Laboratory Test Interferences: Prothrombin Time.) Several manufacturers recommend abrupt discontinuance of heparin without tapering in patients who have an adequate therapeutic response to a coumarin derivative.373,453,459,500 However, concern exists that abrupt discontinuance of heparin may result in a high-risk period for rebound thrombosis, although recommendations to reduce this risk remain to be established. In the absence of such recommendations, some clinicians recommend that heparin infusions be reduced in a gradual fashion such as by reducing the rate by 50% over 6 hours and then discontinuing over the next 12 hours.
Treatment of Venous Thromboembolism
Adults
For full-dose continuous IV infusion therapy for the treatment of venous thrombosis and pulmonary embolism in a 68-kg adult, some manufacturers recommend an initial heparin sodium loading dose of 5000 units given by IV injection, followed by a continuous infusion of 20,000-40,000 units in 1 L of 0.9% sodium chloride injection or other compatible IV solution over 24 hours.373,453,500 The American College of Chest Physicians (ACCP) suggests that therapy with IV heparin sodium may be initiated in a weight-adjusted dosage (loading dose of 80 units/kg followed by a continuous infusion of 18 units/kg per hour) or a fixed dosage (loading dose of 5000 units, followed by a continuous IV infusion of 1000 units/hour).1000 Although the aPTT can be used to monitor either dosage regimen, ACCP states that there is no evidence suggesting that monitoring improves clinical outcomes.1000
For full-dose intermittent IV therapy in a 68-kg adult for the treatment of venous thromboembolism and pulmonary embolism, some manufacturers recommend an initial loading dose of 10,000 units of heparin sodium (either undiluted or diluted in 50 or 100 mL of 0.9% sodium chloride injection), followed by 5000-10,000 units every 4-6 hours.373,500
For full-dose subcutaneous therapy in a 68-kg adult, some manufacturers recommend an initial heparin sodium dose of 5000 units by IV injection, then 10,000-20,000 units in a concentrated solution injected subcutaneously for 1 dose, followed by subcutaneous injection of 8000-10,000 units as a concentrated solution every 8 hours or 15,000-20,000 units as a concentrated solution every 12 hours.453,500 In patients receiving subcutaneous heparin sodium for the treatment of venous thromboembolism in the outpatient setting, ACCP and some manufacturers suggest the use of weight-based dosing (initial dose of 333 units/kg, followed by a dosage of 250 units/kg twice daily) without monitoring rather than a fixed dosage or a weight-adjusted dosage with monitoring.373,1000
In patients in whom long-term warfarin therapy will subsequently be prescribed, ACCP recommends initiating warfarin and heparin together on the first treatment day and overlapping therapy with the 2 drugs for a minimum of 5 days and until the international normalized ratio (INR) is at least 2 for 24 hours or longer.500,1005
When converting to oral dabigatran therapy in patients currently receiving heparin therapy by continuous IV infusion, the first dose of dabigatran should be administered, followed immediately by discontinuance of the heparin infusion; for patients currently receiving intermittently dosed IV heparin therapy, oral dabigatran should be initiated within 2 hours prior to what would have been the time of the next scheduled heparin dose.373
Pediatric Patients
Dosage recommendations in the pediatric population generally are based on clinical experience because of a lack of adequate and well-controlled studies of heparin in these patients.373,500 In children receiving full-dose (therapeutic) heparin therapy, ACCP suggests that dosage be titrated to achieve an anti-factor Xa concentration of 0.35-0.7 units/mL or to prolong the aPTT to a corresponding anti-factor Xa range or to a protamine titration range of 0.2-0.4 units/mL.1013 Because clinical outcome studies have not been conducted in children, the therapeutic range for heparin in neonates and children is mostly derived from experience in adults.1013 Following initial heparin therapy in children with an acute venous thromboembolic event, a low molecular weight heparin or a coumarin anticoagulant (e.g., warfarin) may be initiated, or the patient may continue to receive heparin for ongoing therapy.1013 In children with venous thromboembolism in whom warfarin therapy will subsequently be prescribed, ACCP recommends initiating warfarin on the first treatment day and overlapping therapy with warfarin and heparin for a minimum of 5 days and until the INR is at least 2 for 24 hours or longer.1005
An initial heparin sodium loading dose of 75-100 units/kg (by direct IV injection over 10 minutes) has been suggested in children based on some data indicating that such doses may be more likely to result in therapeutic aPTT values.373,500,503,1013 Following the initial loading dose, a maintenance IV infusion of 25-30 units/kg per hour in infants or 18-20 units/kg per hour in children older than 1 year of age is suggested.373,500,1013 The appropriate maintenance dosage of heparin sodium appears to be age dependent, with infants under the age of 2 months having the highest requirements (e.g., average of 28 units/kg per hour) and older children having lower requirements (e.g., average of 20 units/kg per hour in children older than 1 year of age);373,500,1013 some experts suggest using a dosage of 18 units/kg per hour in older children.503 Although not preferred, a maintenance heparin sodium dosage of 75-100 units/kg every 4 hours by intermittent IV administration has been used.503,1013 ACCP states that the initial dosing strategy in children should be individualized based on consideration of risk factors for bleeding and thrombosis; in general, loading doses should be withheld or reduced if there are substantial bleeding risks, and long-term use of heparin should be avoided in children.1013
Thromboprophylaxis in General Surgery
For fixed low-dose prophylaxis of postoperative deep-vein thrombosis in general surgery patients, the most widely used dosage of heparin sodium has been 5000 units administered subcutaneously 2 hours prior to surgery and every 8-12 hours after surgery for 7 days or until the patient is fully ambulatory, whichever is longer.500 If clinical evidence of thromboembolism develops despite fixed low-dose prophylaxis, full-dose IV or subcutaneous heparin should be initiated.500
Acute Ischemic Complications of ST-Segment-Elevation Myocardial Infarction
As adjunctive therapy with fibrin-selective thrombolytic agents (e.g., alteplase, tenecteplase, reteplase) in patients with ST-segment-elevation MI (STEMI)†, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend IV heparin sodium given in an initial loading dose of 60 units/kg (maximum 4000 units) followed by a continuous infusion of 12 units/kg per hour (maximum 1000 units/hour), adjusted to maintain a therapeutic aPTT of 1.5-2 times the control value or 50-70 seconds for 48 hours or until revascularization.527
In patients with acute MI and concurrent atrial fibrillation, ACCF, AHA, and the Heart Rhythm Society (HRS) recommend continuous IV infusion or intermittent subcutaneous injection of heparin sodium in a dosage sufficient to prolong the aPTT to 1.5-2 times the control value.999
Acute Ischemic Complications of Percutaneous Coronary Intervention
In patients undergoing percutaneous coronary intervention (PCI) who are not receiving concurrent antiplatelet therapy with a GP IIb/IIIa-receptor inhibitor and who have not received prior anticoagulant therapy, ACCF, AHA, and the Society for Cardiovascular Angiography and Interventions (SCAI) suggest administration of a loading dose of 70-100 units/kg of heparin sodium by direct IV injection to achieve an ACT of 250-300 seconds with the HemoTec device or 300-350 seconds with the Hemochron device.994 If prior anticoagulant therapy has been administered in such patients, additional heparin sodium doses (e.g., 2000-5000 units) should be given as needed to achieve an ACT of 250-300 seconds with the HemoTec device or 300-350 seconds with the Hemochron device.994 In patients undergoing PCI who are receiving concurrent therapy with a GP IIb/IIIa-receptor inhibitor and who have not received prior anticoagulant therapy, use of a lower dose of concurrent heparin sodium (50-70 units/kg IV loading dose) targeted to an ACT of 200-250 seconds is suggested.994 If prior anticoagulant therapy has been administered in such patients, additional heparin sodium doses (e.g., 2000-5000 units) should be given as needed to achieve an ACT of 200-250 seconds.994 Lower dosages of heparin may be used in women and geriatric patients undergoing PCI, particularly when heparin is combined with GP IIb/IIIa-receptor inhibitors.455 Heparin sodium should be discontinued after successful PCI procedures; in most cases, the femoral sheath is removed when the ACT falls to less than 150-180 seconds or when the aPTT decreases to less than 50 seconds.994
Acute Ischemic Complications of Non-ST-Segment-Elevation Acute Coronary Syndromes
Adjusted-dose heparin sodium (e.g., 60 units/kg [maximum 4000 units] loading dose followed by continuous IV infusion of 12 units/kg per hour [maximum 1000 units/hr]) is recommended by ACCF, AHA, and ACC to maintain the aPTT between 1.5-2 times the control value in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS; unstable angina or non-ST-segment-elevation MI [NSTEMI]) in addition to aspirin and/or clopidogrel.993 Therapy should be initiated as soon as possible upon presentation.993 Optimum duration of therapy has not been established; in clinical trials, heparin was continued for 2-5 days.993
Disseminated Intravascular Coagulation
When heparin is used for the treatment of disseminated intravascular coagulation (DIC), some clinicians recommend heparin sodium doses of 50-100 units/kg for adults and 25-50 units/kg for children given by IV infusion or IV injection every 4 hours. If there is no improvement after 4-8 hours, the drug should be discontinued.
Cardiac Surgery
The initial dose of heparin sodium recommended by the manufacturers for adults undergoing total body perfusion for open-heart surgery is not less than 150 units/kg.453,459,500 A heparin sodium dose of 300 units/kg is frequently used for procedures estimated to last less than 1 hour and 400 units/kg for those procedures estimated to last longer than 1 hour.453,459,500 Some clinicians recommend that heparin sodium dosage during cardiopulmonary bypass procedures be adjusted to prolong the ACT to 480-600 seconds. In extracorporeal dialysis procedures, the equipment manufacturer's operating instructions should be followed carefully;500 if manufacturer's instructions are not available, an initial heparin sodium dose of 25-30 units/kg, followed by an infusion of 1500-2000 units/hour is suggested based on pharmacodynamic data.373
Cardioversion of Atrial Fibrillation
If heparin is used for the prevention of stroke and systemic embolism in patients undergoing cardioversion for atrial fibrillation or atrial flutter†, the use of full venous thromboembolism treatment dosages is recommended.1007
Thromboembolism During Pregnancy
When heparin is used for thromboprophylaxis during pregnancy†, the drug is usually administered 2-3 times daily in a prophylactic dosage (fixed-dose) or intermediate dosage (dosage adjusted to target a specific anti-factor Xa level).1012 When used in therapeutic dosages, heparin usually is administered by continuous IV infusion with doses adjusted to achieve a target therapeutic aPTT or by twice-daily subcutaneous injection in doses sufficient to achieve a therapeutic aPTT 6 hours after injection.1012
In women with antiphospholipid antibody (APLA) syndrome and a history of multiple pregnancy losses, antepartum administration of subcutaneous heparin sodium in a prophylactic or intermediate dosage has been recommended; low-dose aspirin (75-100 mg daily) should be administered in conjunction with heparin.290,295,299,300,315,1012
ACCF/AHA/HRS state that administration of heparin may be considered during the first trimester and last month of pregnancy in patients with atrial fibrillation and additional risk factors for thromboembolism.999 Heparin sodium may be administered by continuous IV infusion in a dosage sufficient to maintain the aPTT at least 1.5-2 times the control value.996,999 Alternatively, 10,000-20,000 units of heparin sodium may be given subcutaneously every 12 hours with dosage adjusted to maintain the mid-interval aPTT (6 hours after the dose) at 1.5-2 times the control value.999 Coumarin anticoagulant therapy (e.g., warfarin) may be considered during the second trimester in pregnant women with atrial fibrillation who have a high risk for thromboembolism.999
If subcutaneous heparin sodium is used for the prevention of thromboembolism in pregnant women with prosthetic mechanical heart valves, the drug should be initiated in high dosages (17,500-20,000 units every 12 hours) and adjusted to maintain the mid-interval aPTT at least twice the control value or an anti-factor Xa concentration of 0.35-0.7 units/mL throughout pregnancy.1012 Alternatively, 17,500-20,000 units of heparin sodium may be administered every 12 hours and adjusted to maintain the mid-interval aPTT at least twice the control value or an anti-factor Xa concentration of 0.35-0.7 units/mL until week 13 of pregnancy; subsequently, therapy is switched to warfarin until close to delivery when heparin may be resumed.1012
Perioperative Management of Antithrombotic Therapy
If heparin is used for bridging anticoagulation in patients who require temporary interruption of warfarin therapy during surgery or other invasive procedure, ACCP recommends the use of therapeutic dosages (e.g., continuous infusion of heparin adjusted to maintain an aPTT of approximately 1.5-2 times the control value) because of more extensive data and experience; however, other dosage regimens have been used.1004 ACCP suggests that heparin be discontinued approximately 4-6 hours prior to surgery to allow sufficient time for anticoagulant effects to dissipate.1004 Postoperative anticoagulation should be administered with caution and only when hemostasis has been achieved because of the potential for bleeding at the surgical site.1004
Anticoagulation in Blood Transfusions and Blood Samples
When heparin sodium is used as an in vitro anticoagulant in blood transfusions, 7500 units of the drug is usually added to 100 mL of 0.9% sodium chloride injection and 6-8 mL of this solution is added to each 100 mL of whole blood.453,500 When heparin sodium is used as an in vitro anticoagulant for blood samples, 70-150 units is added to each 10-20 mL of whole blood.453,500
Thrombosis Associated with Indwelling Venous or Arterial Devices
When a heparin-containing flush solution is used to maintain patency of indwelling venipuncture devices, a quantity of heparin lock flush solution (e.g., containing 10 or 100 units of heparin sodium per mL) sufficient to fill the device is injected into the lumen of the device after each use, after designated intervals (if the device is not used in the interim), or as necessary.234,462,464,465 While it has been reported that each dose of the solution will maintain anticoagulation within the lumen of the device for up to 4 hours,111,234 longer intervals between instillations of the flush solution (generally every 8-12 hours) are commonly employed when the device is not being used more frequently,111,112,113,114 and flushing with 0.9% sodium chloride injection alone at such intervals also appears to be effective in maintaining patency in venipuncture devices into which blood is not aspirated, at least those placed peripherally.215,216,221,222,223,224,225,227,233,242
When a drug that is incompatible with heparin is to be administered via a venipuncture device in which a heparin-containing flush solution is used, the entire device should be flushed with 0.9% sodium chloride injection prior to and immediately after the incompatible drug is administered.234,462,464 Another dose of heparin lock flush solution may be injected into the device after the second saline flush.234,462,464 When the indwelling venipuncture device is used for repeated withdrawal of blood samples for laboratory analysis and the presence of heparin or 0.9% sodium chloride is likely to interfere with or alter results of the analysis, heparin lock flush solution should be cleared from the device by aspirating and discarding it from the device before withdrawing the blood sample.234,462,464,465 After the blood sample is drawn, another dose of heparin lock flush solution should be injected into the device.219,234,462,464,465
Following injection of heparin lock solution from a single-dose vial into an indwelling venipuncture device, unused portions of the solutions should be discarded.462 The device manufacturer's instructions should be consulted for specific directions.234,462,464 Multiple-dose vials are available for repeated use.464 Since repeated injections of small doses of heparin sodium can alter aPTT results, it is recommended that a baseline aPTT value be obtained prior to insertion of an indwelling venipuncture device.215,220,231,234,462,464
In neonates and children requiring cardiac catheterization via an artery†, ACCP recommends a heparin sodium dose of 100 units/kg as a direct IV injection.1013 Additional doses may be required in prolonged procedures.1013
For thromboprophylaxis in neonates with a central venous access device†, ACCP recommends the use of heparin sodium 0.5 units/kg per hour as a continuous infusion.1013
For thromboprophylaxis of umbilical arterial catheters in neonates†, ACCP suggests the use of low-dose heparin sodium infusion (0.25-1 unit/mL) for a total dosage of 25-200 units/kg per day.1013
For thromboprophylaxis in neonates and children with peripheral arterial catheters, administration of heparin sodium by continuous IV infusion in low dosages (5 units/mL at 1 mL/hour) is recommended by ACCP.1013
Cautions ⬆ ⬇
Hematologic Effects
Hemorrhage, the major adverse effect of heparin, is an extension of the pharmacologic action of the drug and may range from minor local ecchymoses to major hemorrhagic complications. Rarely, hemorrhagic complications may result in death. Bleeding complications occur in approximately 1.5-20% of patients receiving heparin. Major bleeding episodes occur more frequently with full-dose than with low-dose heparin and have been reported more frequently with intermittent IV injection than with continuous IV infusion of the drug. The incidence of major bleeding appears to be similar among patients receiving heparin by continuous IV infusion or subcutaneously.386 Pooled data from a number of clinical trials evaluating IV heparin for the treatment of venous thromboembolism indicate that the rates of major bleeding range from 0-7% and fatal bleeding from 0-2%.386 In patients with ischemic coronary syndromes, the incidence of major bleeding ranges from 0-6.3% during the initial 8 days of treatment and from 0.3-3.2% during subsequent long-term therapy (approximately 0.25-3 months).386 Hemorrhage also has been reported occasionally with repeated administration of heparin lock flush solutions containing low concentrations of heparin sodium (e.g., 10-100 units/mL).214,215,230,235
Patients with renal failure or with a history of recent surgery or trauma may be at increased risk of bleeding complications during therapy with heparin.386 There is some evidence that the risk of heparin-induced hemorrhage may be higher in patients older than 60 years of age, especially in women.500 Bleeding may occur at any site, and some hemorrhagic complications may be difficult to detect.500 GI or urinary tract bleeding during therapy with heparin may indicate the presence of occult lesions.500 Adrenal hemorrhage with acute adrenal insufficiency has occurred during therapy with heparin. Retroperitoneal hemorrhage has been reported in patients receiving anticoagulant therapy, and potentially fatal ovarian (corpus luteum) hemorrhage has also occurred in some women of reproductive age who received short- or long-term anticoagulant therapy.500 The frequency and severity of heparin-associated hemorrhage may be minimized by careful clinical management of the patient. (See Cautions: Precautions and Contraindications.)
Pooled analyses of data from comparative clinical trials evaluating heparin and low molecular weight heparins for the treatment of venous thromboembolism or ischemic coronary syndromes indicate that use of low molecular weight heparin does not result in an increased risk of major bleeding compared with heparin.386
Two forms of acute thrombocytopenia have been reported with heparin. In some patients, thrombocytopenia appears to be caused by a direct, nonimmunologic effect on circulating platelets. In others, the reaction is immune mediated (heparin-induced thrombocytopenia [HIT]) and caused by the development of IgG antibodies to an immune complex that forms between heparin and platelet factor 4; these antibody-bound immune complexes bind to IgG receptors on the surface of platelets, resulting in platelet activation and increased thrombin generation.373,500,502,1006 Thrombocytopenia has been reported with both low-dose and full-dose heparin therapy and does not appear to be dose related. Thrombocytopenia, including accompanying intracranial bleeding and GI hemorrhage, has been reported in patients receiving less than 500 units of heparin sodium daily via heparin lock flush solution.226,229,230 Although the reported incidences are variable (e.g., 0-30%), thrombocytopenia has occurred in about 15% of patients treated with heparin sodium prepared from bovine lung tissue and in about 5% of those treated with heparin sodium prepared from porcine intestinal mucosa. Thrombocytopenia, if it occurs, usually develops 1-20 days after initiation of therapy.90,108 Immune-mediated HIT usually is evident 5-10 days after exposure to heparin, but can occur more rapidly (e.g., within 24 hours) in patients with recent exposure (e.g., within the previous 3 months) to the drug or appear as late as several weeks after discontinuance of therapy.500,1006 Mild thrombocytopenia (platelet count greater than 100,000/mm3) may remain stable or even reverse with continued heparin therapy.90,101,108,500 However, thrombocytopenia of any degree should be monitored closely since HIT can sometimes lead to the development of serious, sometimes fatal, thrombotic events.101,108,500,502 Heparin therapy should generally be discontinued if substantial thrombocytopenia (platelet count less than 100,000/mm3) or HIT (with or without thrombosis) occurs.101,108,500,1006
HIT is a serious complication of heparin therapy that can lead to life- or limb-threatening venous and arterial thrombosis (e.g., cerebral vein thrombosis, limb ischemia, acute myocardial infarction [MI], stroke, gangrene of the extremities [possibly requiring amputation], mesenteric thrombosis).214,215,228,229,230,232,500,502,1006 Localized or disseminated thromboses associated with HIT have occurred in patients receiving heparin,90,101,108,109 even in the low concentrations used in heparin lock flush solution.214,215,226,228,1006 HIT-associated thrombosis develops as a result of in vivo platelet aggregation induced by heparin and can occur at almost any vascular location.500,502,1006 (See Cautions: Precautions and Contraindications.)
Sensitivity Reactions
Allergic reactions to heparin occur rarely. Hypersensitivity, which can be generalized, may be manifested by chills, fever, pruritus, urticaria, asthma, rhinitis, lacrimation, headache, nausea, vomiting, and anaphylactoid reactions including shock. Allergic vasospastic reactions have been reported with heparin. These reactions, if they occur, generally develop 6-10 days after initiation of heparin and last 4-6 hours. The reactions frequently occur in a limb where an artery has been recently catheterized. The affected limb is painful, ischemic, and cyanosed. If heparin is continued, generalized vasospasm with cyanosis, tachypnea, feelings of oppression, and headache may occur. Protamine sulfate has no effect on these reactions.
Itching and burning, especially of the plantar side of the feet, has occurred during heparin therapy and may be caused by a similar allergic vasospastic reaction. Chest pain, hypertension, arthralgia, and/or headache have also been reported in the absence of definite peripheral vasospasm.
Local Effects
Deep subcutaneous injection of heparin may rarely cause local irritation, erythema, mild pain, hematoma, ulceration, or cutaneous and subcutaneous necrosis (sometimes requiring skin grafts). Local irritation and erythema also have been reported with heparin lock flush solution.462,464 Histamine-like reactions have also been reported at the site of injection. A slightly lower incidence of local reactions has been reported following deep subcutaneous injection of heparin calcium (no longer commercially available in the US) than that reported following deep subcutaneous injection of equal doses of heparin sodium; this may be due to the smaller volume of heparin calcium required.
Hepatic Effects
Increased serum concentrations of AST (SGOT) and ALT (SGPT), without increased serum concentrations of bilirubin or alkaline phosphatase, have been reported in a high percentage of patients following subcutaneous or IV administration of heparin;100,101,234,365 transient increases in serum LDH concentrations have also occurred in some patients receiving the drug.100 Increased concentrations of AST and ALT have also been reported following administration of heparin to healthy individuals.100,101,234 A reversible cholestatic reaction without jaundice, manifested by increased serum aminotransferase (ALT, AST) and alkaline phosphatase concentrations, also has been reported in a few patients receiving heparin therapy.365 It is not known whether elevated serum aminotransferases in patients receiving heparin represent hepatic toxicity, drug-induced laboratory test interference, or nonspecific stimulation of hepatic enzymes.100,101,366 (See Laboratory Test Interferences.) Since aminotransferase determinations are important in the differential diagnosis of MI, liver disease, and pulmonary emboli, elevation of these enzymes during heparin therapy should be interpreted with caution.101,234
Other Adverse Effects
Osteoporosis and spontaneous fractures of the vertebral column have been reported rarely in patients receiving large daily dosages (10,000 units or more) of heparin sodium for 3 months or longer. Suppression of aldosterone synthesis; priapism; delayed, transient alopecia; and rebound hyperlipemia following discontinuance of heparin therapy have also been reported rarely in patients receiving the drug.373,500
Precautions and Contraindications
All patients should be screened prior to initiation of heparin therapy to rule out bleeding disorders. In preoperative patients, the prothrombin time (PT), activated partial thromboplastin time (aPTT), hematocrit, and platelet count should be determined prior to surgery; coagulation tests should be normal or only slightly elevated before low-dose heparin therapy is instituted. Although monitoring of blood coagulation tests is useful for assuring adequate dosage during full-dose heparin therapy, coagulation test results do not always correlate with the frequency of bleeding complications. Heparin should be used with extreme caution whenever there is an increased risk of hemorrhage. Factors reported to increase the risk of hemorrhage during heparin therapy include concurrent administration of some drugs (see Drug Interactions); subacute bacterial endocarditis; arterial sclerosis; dissecting aneurysm; increased capillary permeability; presence of inaccessible ulcerative GI lesions; diverticulitis; ulcerative colitis; hemorrhagic blood dyscrasias (e.g., hemophilia, some vascular purpuras, thrombocytopenia); menstruation; ovulation; threatened abortion; severe renal, hepatic, or biliary disease; hypertension; indwelling catheters; eye, brain, or spinal cord surgery; continuous tube drainage of the stomach or small intestine; and spinal tap or spinal anesthesia.
If hemorrhage occurs, heparin should be discontinued immediately. Nosebleed, hematuria, or tarry stools may be noted as the first sign of bleeding or overdosa easy bruising or petechiae may precede frank bleeding.500 Discontinuance of heparin will usually correct minor bleeding or overdosage within a few hours. If severe hemorrhage or overdosage occurs, protamine sulfate should be administered immediately. Blood transfusions may also be required in patients with massive blood loss. If signs and symptoms of acute adrenal hemorrhage and insufficiency occur, plasma cortisol concentrations should be measured and vigorous therapy with IV corticosteroids should be initiated after discontinuing heparin. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may be fatal.500
Heparin is contraindicated in patients with severe thrombocytopenia462,464,500,504,505,506 or a history of HIT or HIT with thrombosis.373 If HIT with or without thrombosis is diagnosed or strongly suspected during heparin therapy, all sources of heparin (including heparin flushes) should be discontinued and an alternative (nonheparin)502,1006 anticoagulant (e.g., argatroban, bivalirudin) substituted.373,405,406,407,408,462,464,500,502,1006 Conversion to warfarin therapy (for longer-term anticoagulation) should be initiated only after substantial recovery from acute HIT has occurred (i.e., platelet counts at least 150,000/mm3) with a nonheparin anticoagulant.1006 The manufacturer recommends against future use of heparin in patients who experience HIT, particularly within 3-6 months following the event and if HIT antibodies are still present.500 HIT with or without thrombosis also can occur up to several weeks following discontinuance of heparin therapy.471 Patients who are found to have thrombocytopenia or thrombosis after discontinuance of heparin should be evaluated for HIT and HIT with thrombosis.471 Although there is some uncertainty regarding the risk-to-benefit ratio of platelet count monitoring in patients receiving heparin, the American College of Chest Physicians (ACCP) suggests that platelet counts may be monitored in those who are considered to be at high risk (higher than 1%) of developing HIT; for those considered to be at low risk (less than 1%), platelet count monitoring generally is not recommended.1006
Patients with familial antithrombin III deficiency may appear to be resistant to the effects of heparin, since adequate levels of antithrombin III are necessary for the drug's anticoagulant effect. Increased resistance to the antithrombotic effects of heparin has been reported in febrile patients, in postoperative patients, and in some patients with MI, pulmonary embolism, thrombophlebitis, infections with thrombosing tendencies, or extensive thrombotic disorders, especially in conjunction with malignant neoplasms. This phenomenon appears to be caused by alterations in the physiology of the patient and pharmacokinetics of the drug, and larger doses of heparin may be required during initial therapy to achieve an anticoagulant response in these patients.
Fatal medication errors have occurred as a result of confusion between different formulations of heparin, in particular with heparin sodium injection and catheter lock flush vials.472,500 At least 3 infant deaths have been reported following inadvertent administration of heparin sodium injection 10,000 units/mL instead of HEP-LOCK U/P (heparin lock flush solution) 10 units/mL.472,500 Heparin sodium injection should not be used as a catheter lock flush product.373,500 To minimize the risk of medication errors, clinicians should take appropriate measures to carefully distinguish between heparin formulations and review all labels for correct drug name, strength, and volume prior to dispensing and administering the drug.472,500,501 Dispensing errors involving heparin sodium injection and HEP-LOCK U/P should be reported to the manufacturer (800-ANA-Drug or 800-262-3784) or the FDA MedWatch program by phone (800-FDA-1088 or online at [Web].
Heparin is generally contraindicated in patients who are hypersensitive to the drug or to pork products.373 Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations.500
Heparin is contraindicated in patients with uncontrollable bleeding, unless such bleeding is secondary to disseminated intravascular coagulation. The drug is also contraindicated whenever suitable blood coagulation tests cannot be performed at required intervals;101,234,373,500 however, this is not generally a contraindication for fixed low-dose heparin therapy, since monitoring of coagulation tests is not usually required when fixed low-dose therapy is used in patients with normal coagulation parameters.101,234,373,500
Some commercially available formulations of heparin sodium injection contain sodium metabisulfite, a sulfite that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
When heparin is used in combination with dihydroergotamine, the usual cautions, precautions, and contraindications associated with dihydroergotamine must be considered in addition to those associated with heparin. The potential risk of arterial vasospasm should be considered in patients receiving combined therapy with these drugs. .
Pediatric Precautions
There are no adequate and well-controlled studies evaluating the use of heparin in pediatric patients.500
Some commercially available heparin sodium injections and heparin lock flush solutions contain benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with serious toxicity (e.g., “gasping syndrome”) in pediatric patients.123,124,125,126,127,500 Toxicity appears to result from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these patients, and may be more likely to occur in neonates and low-birthweight infants.123,124,125,126,127,378,500 When heparin sodium injection is required in neonates and infants, the manufacturer states that a preservative-free formulation should be used.373,500 When heparin lock flush is required in neonates, a preservative-free formulation should be used.378,462 The American Academy of Pediatrics (AAP) states that use of preservative-containing flush solutions (i.e., with benzyl alcohol) clearly should be avoided in neonates; however, the AAP further states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use in neonates.378 Although the recommended dosage range for heparin includes amounts of benzyl alcohol well below that associated with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is unknown.500 If other benzyl alcohol-containing preparations are to be used in a patient, clinicians should take into account the total daily metabolic load of benzyl alcohol from all sources.500
Fatalities have occurred in pediatric patients, including neonates, as a result of medication dispensing errors.472,500 Clinicians should take appropriate precautions when dispensing and administering the drug.500 (See Cautions: Precautions and Contraindications.)
The use of heparin to maintain patency of umbilical-artery catheters reportedly has been associated with an increased risk of germinal matrix-intraventricular hemorrhage in low-birthweight neonates;119 however, a causal relationship has not been definitely established, and well-controlled studies are needed to further evaluate this finding.119,120,121,122 Because of the potential risk of systemic anticoagulation, heparin lock flush solutions containing heparin sodium 100 units/mL should be avoided in neonates and in infants who weigh less than 10 kg.464 Caution also is advised when using heparin lock flush solutions containing 10 units/mL in premature infants who weigh less than 1 kg and are receiving frequent flushes.462,464
Geriatric Precautions
A higher incidence of bleeding has been reported in patients older than 60 years of age, especially women.471 Clinical studies indicate that lower dosages of heparin may be appropriate in these patients.471 (See Dosage and Administration: Dosage.)
Pregnancy, Fertility, and Lactation
Pregnancy
Increased fetal resorptions have been observed in animals when heparin was administered during the period of organogenesis in dosages higher than the maximum human dosa there are no adequate and well-controlled studies to date using heparin in pregnant women.500 Published reports have not shown any evidence of a teratogenic potential or other adverse fetal effects when the drug is used during pregnancy; because heparin does not cross the human placenta, any fetal complications that may occur are likely to be related to other indirect factors (e.g., severe maternal disease).284,500
Long-term (e.g., longer than 1 month) heparin therapy during pregnancy can result in maternal osteopenia and osteoporosis, and prophylactic calcium and vitamin D supplementation has been suggested to reduce this risk.284,285,286,287,288,289,290,292 At least one case of fatal cerebral hemorrhage has occurred in a woman receiving heparin and aspirin to prevent pregnancy loss following in vitro fertilization.294 (See Uses: Complications of Pregnancy.)
Heparin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus; if needed, use of a preservative (benzyl alcohol)-free formulation is recommended.500 When anticoagulant therapy is required in pregnant women, ACCP generally recommends the use of a low molecular weight heparin because of a more favorable adverse effect profile.1012 For information on the prophylactic use of heparin to improve pregnancy outcomes in certain women at risk (e.g., those with antiphospholipid syndrome), see Uses: Complications of Pregnancy.
Lactation
Because of its high molecular weight, heparin is not likely to be distributed into human milk; any heparin that is ingested during breastfeeding would not be absorbed by a nursing infant.500 However, if benzyl alcohol is present in maternal serum, it is likely to distribute into human milk and be absorbed by a nursing infant.500 The manufacturer recommends caution if heparin is used in nursing women.500 ACCP recommends that heparin be continued in nursing women who are already receiving such therapy.1012
If heparin therapy is required in nursing women, use of a preservative (benzyl alcohol)-free formulation is recommended.500
Drug Interactions ⬆ ⬇
Drugs Affecting Platelet Function
Drugs that affect platelet function (e.g., aspirin and other nonsteroidal anti-inflammatory agents, dextran, dipyridamole, phenylbutazone [no longer commercially available in the US], hydroxychloroquine, GP IIb/IIIa-receptor inhibitors such as abciximab, eptifibatide, and tirofiban) may increase the risk of hemorrhage and should be used with caution in patients receiving heparin.
Thrombolytic Agents
Concomitant therapy with heparin and/or platelet-aggregation inhibitors has been used with thrombolytic agents to prevent reocclusion following lysis of coronary artery thrombi. However, since such therapy has not been shown to be of unequivocal benefit and may increase the risk of bleeding complications, use of anticoagulants concomitantly with thrombolytic therapy should be individualized and careful monitoring is advised. Some evidence suggests a narrow margin of safety for upward adjustment of heparin dosage, and the need for serial monitoring of activated partial thromboplastin time (aPTT), in patients receiving heparin concurrently with thrombolytic therapy for acute myocardial infarction (MI).281,282 (See Uses: Acute Ischemic Complications of ST-Segment-Elevation Myocardial Infarction.)
Dihydroergotamine Mesylate
When used in combination with heparin, dihydroergotamine appears to potentiate the antithrombogenic effects of heparin by helping to reduce factors that contribute to venous thrombus formation.51,101,102,103 As a result of its vasoconstrictor effect, dihydroergotamine accelerates venous return, reduces venous stasis and pooling, and may also indirectly help to prevent damage to venous endothelium caused by excessive dilation.51,101,102,103,104 Therefore, concomitant use of dihydroergotamine and heparin may help to prevent deep-vein thrombosis.51,101,103
Concomitant subcutaneous administration of dihydroergotamine mesylate with heparin sodium does not appear to affect the pharmacokinetics of heparin.101,103 Concomitant subcutaneous administration of the drugs reportedly decreases peak plasma concentrations of dihydroergotamine and decreases the rate of absorption of dihydroergotamine compared with administration of dihydroergotamine alone; however, the area under the concentration-time curve of dihydroergotamine is generally unaffected.101
Other Drugs
Although some reports suggest that IV nitroglycerin may antagonize the anticoagulant effect of heparin when these drugs are administered concomitantly,155,156,245,246 such antagonism has not been confirmed in other studies.247,248,249,250,251,252 Limited data suggest that nitroglycerin-induced heparin resistance, if it occurs, may be manifested only at high nitroglycerin dosages or infusion rates (e.g., greater than 350 mcg/minute) and may possibly be related to a nitroglycerin-induced abnormality in antithrombin III (heparin cofactor).253,254,255 Further study is required to confirm possible IV nitroglycerin-induced heparin resistance in patients receiving these drugs concomitantly and, if confirmed, to elucidate the potential clinical importance of such an interaction.246,248,250,253,254,255 Meanwhile, it has been suggested that patients receiving heparin and IV nitroglycerin concomitantly be monitored closely to avoid inadequate anticoagulation.155,156,256
Cardiac glycosides, nicotine, quinine, tetracyclines, and antihistamines reportedly may interfere with the anticoagulant effect of heparin. Although there is some experimental evidence that heparin may antagonize the action of corticosteroids, corticotropin, and insulin, these effects have not been definitely established.
The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with familial antithrombin III deficiency.373 To avoid bleeding, at least one manufacturer recommends a reduced dosage of heparin during concurrent treatment with antithrombin III.373
Other Information ⬆ ⬇
Laboratory Test Interferences
Prothrombin Time
Heparin prolongs the prothrombin time (PT), and caution should be observed in evaluating the test in patients receiving a coumarin or indandione derivative and heparin. Valid PT determinations can usually be made during concurrent therapy if blood samples for the test are drawn at least 4-6 hours after an IV dose or 12-24 hours after a subcutaneous dose of heparin. The PT may not be significantly prolonged by heparin when the drug is administered by continuous IV infusion and blood samples for the test can usually be obtained at any time during the infusion.
Other Laboratory Tests
Heparin reportedly interferes with the sulfobromophthalein test by increasing the color intensity of the dye in serum and causing a shift in the absorption peak from 580 to 595 nm.
Heparin interferes with competitive protein binding methods for serum thyroxine determinations resulting in falsely elevated concentrations. Radioimmunoassay and protein bound iodine methods do not appear to be affected by heparin.
When heparin is used as an in vitro anticoagulant, leukocyte counts should be done within 2 hours after addition of heparin. Heparinized blood should not be used for erythrocyte sedimentation rates, platelet counts, or erythrocyte fragility tests and is unsuitable for tests involving complement or isoagglutinins.
Heparin may cause false elevations in plasma AST (SGOT) concentrations using an Ektachem dry-chemistry system analyzer.366 Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction (MI), liver disease, and pulmonary emboli, elevation of these enzymes during heparin therapy should be interpreted with caution.101,234,373
Pharmacology
Anticoagulant Effect
Heparin acts as a catalyst to markedly accelerate the rate at which antithrombin III (heparin cofactor) neutralizes thrombin and activated coagulation factor X (Xa). Antithrombin III generally neutralizes these coagulation factors by slowly and irreversibly complexing stoichiometrically with them; however, in the presence of heparin, it neutralizes these factors almost instantaneously. Although the exact mechanism of action has not been fully elucidated, heparin apparently binds to antithrombin III and induces a conformational change in the molecule which promotes its interaction with thrombin and factor Xa. In the presence of heparin, antithrombin III also neutralizes activated coagulation factors IX, XI, XII, and plasmin.
With low-dose heparin therapy (see Dosage and Administration: Dosage), anticoagulation appears to result from neutralization of factor Xa which prevents the conversion of prothrombin to thrombin. Low doses of heparin have very little effect on thrombin and exert a measurable antithrombogenic effect only if thrombin formation has not already occurred. With full-dose heparin therapy (see Dosage and Administration: Dosage), anticoagulation appears to result primarily from neutralization of thrombin which prevents the conversion of fibrinogen to fibrin. Full-dose heparin therapy also prevents the formation of a stable fibrin clot by inhibiting activation of fibrin stabilizing factor. In contrast to coumarin and indandione derivatives, heparin has an anticoagulant effect both in vitro and in vivo. Low-dose or full-dose heparin therapy inhibits thrombus formation when stasis is induced, and full-dose therapy may prevent extension of existing thrombi. Heparin has no fibrinolytic activity and cannot lyse established thrombi.
In adequate dosage, protamine sulfate neutralizes the anticoagulant effect of heparin. Although there is no significant difference in the anticoagulant effectiveness between heparin derived from porcine intestinal mucosa or bovine lung tissue, slightly different amounts of protamine sulfate are required to neutralize one unit of heparin calcium (no longer commercially available in the US) derived from porcine intestinal mucosa or one unit of heparin sodium derived from bovine lung tissue or porcine intestinal mucosa.
Because heparin acts on blood coagulation factors that are involved in both extrinsic and intrinsic coagulation, full-dose heparin therapy produces prolongation of several coagulation assays including the activated coagulation time (ACT), activated partial thromboplastin time (aPTT), plasma recalcification time, prothrombin time (PT), thrombin time, and whole blood clotting time. Coagulation test results are generally unaffected or only minimally prolonged by low-dose heparin therapy. Heparin sodium lock flush solution does not induce systemic anticoagulant effects when administered in single doses of 10 or 100 units/mL to maintain the patency of IV injection devices.
Other Effects
In vivo, heparin clears lipemic plasma by stimulating the release and/or activation of lipoprotein lipase which hydrolyzes triglycerides to free fatty acids and glycerol. This effect may occur following doses of heparin that are smaller than those required to produce anticoagulant effects. Rebound hyperlipemia has been reported following a period of heparin-induced plasma clearing. Protamine sulfate inhibits the plasma-clearing effect of heparin.
Heparin has been reported to increase, decrease, or have no effect on platelet adhesiveness, aggregation, and release reaction. Many reports are based on in vitro studies that were performed under various conditions, and results do not necessarily correspond to in vivo effects of heparin on platelets. (See Cautions: Hematologic Effects.) Various other pharmacologic actions including anti-inflammatory, diuretic, antimetastatic, antiviral, and antienzymatic effects have been attributed to heparin; however, most of these reports are based on animal studies and their clinical importance has not been established.
Pharmacokinetics
Absorption
Heparin is not absorbed from the GI tract and must be administered parenterally. The onset of anticoagulant activity is immediate following direct IV injection or the start of continuous IV infusion of full doses of heparin. There may be considerable interpatient variation in the extent of absorption following deep subcutaneous injection of heparin; however, onset of activity usually occurs within 20-60 minutes. Results of preliminary studies indicate that the rate and extent of absorption are lower following deep subcutaneous injection of heparin calcium (no longer commercially available in the US) than following deep subcutaneous injection of equal doses of heparin sodium.
Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.500
Distribution
Heparin appears to be extensively bound to low-density lipoprotein, globulins, and fibrinogen. The drug does not cross the placenta and is not distributed into milk.
Elimination
The plasma half-life of heparin averages 1-2 hours in healthy adults. However, the half-life of the drug increases with increasing doses. Following IV administration of heparin sodium 100, 200, or 400 units/kg, the plasma half-life of the drug averages 56, 96, and 152 minutes, respectively. Several studies using heparin sodium have shown that the drug has a shorter plasma half-life in patients with pulmonary embolism than in healthy individuals or patients with other thrombotic disorders. The plasma half-life of the drug is also decreased in patients with liver impairment but may be prolonged in cirrhotic patients. In anephric patients or patients with severe renal impairment, the half-life of heparin may be slightly prolonged.
The metabolic fate of heparin has not been fully elucidated, but the drug appears to be removed from the circulation mainly by the reticuloendothelial system and may localize on arterial and venous endothelium. Although there is no reproducible evidence, it has been suggested that heparin may be partially metabolized in the liver to uroheparin, which is partially desulfated heparin. A small fraction of each dose of heparin appears to be excreted in urine as unchanged drug. Heparin is not removed by hemodialysis.
Chemistry and Stability
Chemistry
Heparin is an anionic, sulfated glycosaminoglycan present in mast cells. Heparin is a heterogeneous molecule with an average molecular weight of about 12,000. Heparin is commercially available as the sodium salt. Heparin sodium is prepared from either porcine intestinal mucosa or bovine lung tissue.
In most countries, potency of heparin is determined using a World Health Organization (WHO) reference standard and is expressed in international units.490,491 In the US, the potency of heparin previously was standardized according to a USP reference standard that was expressed in USP Heparin Units and required a potency of not less than 140 units/mg of heparin. On October 1, 2009, USP implemented a new reference standard for heparin to ensure the purity, consistency, and safety of heparin-containing products in the US supply chain.489,490,491 This new compendial standard was developed largely in response to a heparin contamination problem that occurred in 2007-2008.476,489 Included in the updated standard is a new potency test method (chromogenic anti-Factor IIa test) that can detect impurities in heparin preparations and a new potency reference standard that will harmonize the USP Heparin Unit with the WHO international unit.489,490,491 As a result of these changes, heparin produced under the new USP standard is approximately 10% less potent, unit for unit, than heparin prepared under the previous USP standard.489,490 (See Dosage and Administration: Dosage.) A revised potency limit of not less than 180 Heparin Units per mg also has been established by USP.492
Heparin sodium (the calcium salt of heparin is no longer commercially available in the US) occurs as a white or pale-colored, amorphous, hygroscopic powder that may have a faint odor and is soluble in water and practically insoluble in alcohol. Heparin sodium injection is a clear, colorless to slightly yellow solution with a pH of 5-8; sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH. Heparin lock flush solution is a sterile isotonic or hyperosmotic solution of heparin sodium injection adjusted to a pH of 5-7.5 with sodium hydroxide and/or hydrochloric acid.462,464 Some commercially available heparin sodium injections or flush solutions have been made isotonic by the addition of sodium chloride and may contain benzyl alcohol or methylparaben and propylparaben as preservatives.
Commercially available solutions of heparin sodium in 0.45% sodium chloride, 0.9% sodium chloride, or 5% dextrose injection have osmolalities of 155, 378, or 287 mOsm/L, respectively.504,505,506
Stability
Most commercially available heparin sodium injections and lock flush solutions should be stored at a temperature of 20-25°C.373,462,464,500 Commercially available injections of heparin sodium in 5% dextrose or in 0.45 or 0.9% sodium chloride should be stored at 20-25°C and protected from freezing.504,505,506
Commercially available premixed IV solutions with heparin sodium injection are provided in containers fabricated from specially formulated PVC.504,505 Water can permeate from inside the containers into the overwrap, but not in amounts sufficient to substantially affect the solution.504,506 Solutions in contact with the plastics can leach out some of their chemical components in very small amounts within the expiration period of the injection; however, safety of the plastics has been confirmed in animals according to USP biological tests for plastic containers.504,505
Heparin is strongly acidic and reacts with certain basic compounds resulting in a loss of pharmacologic activity. Although results of some compatibility studies are conflicting, heparin has been reported to be stable for 24 hours at room temperature in lactated Ringer's injection. Heparin should not be mixed with ciprofloxacin, doxorubicin, droperidol, or mitoxantrone since a precipitate may be formed. Heparin is potentially physically and/or chemically incompatible with other drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific information on the stability and compatibility of heparin.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Heparin Sodium
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | Injection (porcine intestinal mucosa) | 1000 units/mL* | Heparin Sodium Injection | |
| | 5000 units/mL* | Heparin Sodium Injection | |
| | 10,000 units/mL* | Heparin Sodium Injection | |
| | 20,000 units/mL* | Heparin Sodium Injection | |
| Solution, lock flush (porcine intestinal mucosa) | 10 units/mL (10, 20, 30, 50, 100, 300 units)* | Heparin Lock Flush Solution | |
| | 100 units/mL (100, 200, 300, 500, 1000, 3000 units)* | Heparin Lock Flush Solution | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Heparin Sodium (Preservative-free)
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | Injection (porcine intestinal mucosa) | 1000 units/mL* | Heparin Sodium Injection | Pfizer |
| | 10,000 units/mL* | Heparin Sodium Injection | |
| Solution, lock flush (porcine intestinal mucosa) | 10 units/mL (10, 30, 50, or 100 units)* | HepFlush®-10 | APP Pharmaceuticals |
| | | Heparin Lock Flush Solution | |
| | 100 units/mL (100, 300 or 500 units)* | Heparin Lock Flush Solution | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Heparin Sodium in Dextrose
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | Injection, for IV infusion (porcine intestinal mucosa) | 40 units/mL (20,000 units) Heparin Sodium in 5% Dextrose* | Heparin Sodium 20,000 units in 5% Dextrose Injection | |
| | 50 units/mL (12,500 units) Heparin Sodium in 5% Dextrose* | Heparin Sodium 12,500 units in 5% Dextrose Injection | |
| | 50 units/mL (25,000 units) Heparin Sodium in 5% Dextrose* | Heparin Sodium 25,000 units in 5% Dextrose Injection | |
| | 100 units/mL (10,000 units) Heparin Sodium in 5% Dextrose* | Heparin Sodium 10,000 units in 5% Dextrose Injection | |
| | 100 units/mL (25,000 units) Heparin Sodium in 5% Dextrose* | Heparin Sodium 25,000 units in 5% Dextrose Injection | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Heparin Sodium in Sodium Chloride
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
Only references cited for selected revisions after 1984 are available electronically.
50. Kakkar VV, Stamatakis JD, Bentley PG et al. Prophylaxis for postoperative deep-vein thrombosis: synergistic effect of heparin and dihydroergotamine. JAMA . 1979; 241:39-42. [PubMed 758493]
51. Sagar S, Nairn D, Stamatakis JD et al. Efficacy of low-dose heparin in prevention of extensive deep-vein thrombosis in patients undergoing total-hip replacement. Lancet . 1976; 1:1151-4. [PubMed 58199]
90. Bell WR, Royall RM. Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J Med . 1980; 303:902-7. [PubMed 6997743]
100. 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. [PubMed 6712030]
101. Sandoz Pharmaceuticals Corporation. Embolex® (dihydroergotamine mesylate and heparin sodium; with lidocaine hydrochloride) injection prescribing information. East Hanover, NJ; 1987 Jun 26.
102. Multicenter Trial Committee. Prophylactic efficacy of low-dose dihydroergotamine and heparin in postoperative deep venous thrombosis following intra-abdominal operations. J Vasc Surg . 1984; 1:608-16. [PubMed 6389909]
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