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 adults(112)(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 vasculature(297)(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)
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 overdosage; 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 thrombocytopenia(462)(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 dosage; 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)
Go to
Drug Interactions [DI]
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)
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.
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.