Heparin dosing

I. Introduction

Unfractionated heparin is the cornerstone for the treatment of acute venous thromboembolism. Although heparin is highly effective, it is always associated with some risk of hemorrhage. Published reports also have described failures of heparin therapy caused by subtherapeutic doses. When heparin is given by continuous IV infusion and the dose is regulated with an appropriate clotting time test, the incidence of serious hemorrhage is reduced and therapeutic efficacy is assured.

Few other medications with the toxicity of heparin that have been available for clinical use for so long have such a lack of uniformity in dosing and monitoring recommendations. Heparin has traditionally been dosed with an IV bolus dose of 5,000 to 10,000 units of heparin, followed by an infusion of 1,000 units per hour. Others have advocated that a more rational method of initiating therapy is to begin with a loading dose of 50-100 units/kg of heparin followed by a constant infusion of 15-25 units/kg/hr. Chenella, et al have described a method for determining initial heparin infusion rates based on the patient's individually determined volume of distribution (blood volume).

Indications

• Venous thromboembolism
  Several studies have provided evidence that, compared to standard care, weight-based dosing of heparin resulted in a shorter time to achieve therapeutic aPTT and fewer bleeding complications. Long-term follow-up has demonstrated a lower rate of recurrent thromboembolism for up to 3 months, giving added importance to accurate dosing in the early phases of treatment.

  The optimal duration of heparin therapy for DVT is still uncertain. Traditionally, heparin is administered for 10 days with warfarin initiated on day 5. Studies in patients with acute DVT have established the safety and efficacy of a 4-5 day course of heparin therapy with warfarin started on day 1.

• Unstable angina
  Unstable angina is a critical phase of coronary heart disease with high risk of myocardial infarction and death. One of the postulated mechanisms of UA is a cyclic formation, dissolution and reformation of clots. Therefore, full-dose heparin therapy is a primary intervention in unstable angina. Studies have shown that steady-state heparin dose requirements are significantly less in patients with CAD compared with patients DVT, suggesting that different dosing nomograms are needed for each condition.

• Acute myocardial infarction
  The role of heparin in conjunction with thrombolytic therapy for the management of patients with acute MI continues to be controversial. Many issues, including the possible benefits and risks of this therapy, are unresolved. The rationale for administration of heparin following thrombolytic therapy is to maintain patency, this appears to be most important for the shorter-acting TPA. Based on the current evidence, it is reasonable to administer Intravenous heparin with either streptokinase or TPA.

• Transient ischemic attack
  Although platelet aggregation is thought to be the primary cause of TIA, there is some evidence that anticoagulants may reduce the rate of TIA's in patients receiving aspirin who remain symptomatic. Less intensive heparin therapy is recommended in treatment of TIA.

• Cerebral ischemic infarction
  The efficacy of heparin in the acute phase of ischemic cerebral vascular accident is unknown, given the studies performed so far. If heparin is to be used, it should only be initiated after a CAT scan has made certain that a cerebral hemorrhage has not occured. As with TIA, less intensive heparin therapy is recommended in treatment of stroke.

II. Monitoring parameters

1. The following patient parameters should be monitored during heparin therapy:
   
   1. aPTT, obtain before initiation of heparin, every six hours thereafter until stable, then daily.
      A patient is considered stabilized when two aPTT's drawn 24 hours apart are within the therapeutic range.
   2. Platelet count, daily.
      Heparin can cause a severe and potentially fatal form of thrombocytopenia commonly referred to as HIT. Although HIT typically occurs 2 to 5 days after heparin exposure, it can occur at any time.
   3. Prothrombin time, daily.
   4. Hematocrit, stool guaiac, and urinalysis (for hematuria), daily.
   5. Concurrent drug therapy: aspirin, dipyridamole, NSAID's.
      Avoid the use of aspirin and aspirin containing drugs during heparin therapy. Aspirin inhibits platelet function. Current evidence indicates that aspirin can increase the risk of bleeding in patients anticoagulated with heparin.

2. Therapeutic range
   The recommended therapeutic range for the treatment of venous thrombosis is based on studies which demonstrated that thrombus extension is prevented by a heparin dose that prolonged the aPTT ratio to 1.5 to 2.5, corresponding to a heparin level of 0.2 to 0.4 units/ml.

   The "control" value used to determine the ratio is poorly defined, it may be the mean value of the normal range for the aPTT, or the patient's baseline aPTT (the aPTT measured before any heparin). Use of the patient's baseline as the control has gained popularity based on the fact that many patients undergoing thrombotic episodes have shortened aPTTs.

   The heparin concentration required to yield a therapeutic effect varies widely between patients. Studies by Cipolle et al, have found that the baseline PTT value accounts for 80% of this variability, reflecting individual differences in clotting factor concentrations and activities. Therefore, a tailored therapeutic range, based on the patient's pretreatment PTT, is likely to be more appropriate than one derived from the mean PTT pooled from dissimilar patients.

   Unfortunately, the different commercial aPTT reagents vary in their responsiveness to heparin. An approximation of the therapeutic range of 0.2 to 0.4 units/ml can be made by testing the aPTT reagent in a plasma system that has been calibrated by addition of a range of clinically relevant concentrations of heparin. This heparin response curve can then be entered into the Kinetics program and used as the basis for dosage adjustments (highly recommended!).

3. Initiating warfarin concurrently with heparin
   The effect of warfarin on the aPTT is not well documented, although it appears that the aPTT is increased following initiation of warfarin and this effect may be cumulative with successive doses. Some patients may be at risk of over-coagulation when heparin and warfarin are combined.

   Many clinicians reduce heparin dosage when warfarin is initiated in anticipation of an increase in the aPTT.

III. Precautions

1. Draw aPTT at steady state
   When the aPTT is checked at 6 hours or longer after a dosage change, steady-state kinetics can be assumed. Non-steady-state analysis can lead to erroneous dosing calculations.

2. Adjust dosages cautiously
   Dosage changes must be made slowly, and the aPTT must be checked every six hours until stable, then daily during the course of therapy. Close monitoring of the patient is essential. Since the aPTT response to changes in heparin infusion rates is not always linear the dosage adjustments should be made in small increments of 100-200 units/hr.
   

   Heparin dose is clearly the most important determinant of minor bleeding episodes. When examined on a unit-per-kg per-hour basis, there is over a 3-fold increase in the risk of bleeding in patients receiving 25 units/kg/hr as compared to patients who receive 15 units/kg/hr.

   Aging is a risk factor for total and major bleeding complications. Because of age-related changes in pharmacokinetic characteristics of heparin, aging is associated with an increase in heparin levels after standard doses. Heparin dose requirements are decreased in the elderly.

3. The major risk factors for hemorrhage from heparin therapy are listed below:
   1. Age over 60
   2. Recent surgery
   3. Trauma (or risk of trauma)
   4. Severe hypertension
   5. Peptic ulcer disease (or history of ulcers)
   6. Drugs which offset platelet function:Aspirin, dipyridamole, NSAID's
   7. Presence of any potential bleeding site
   8. Congenital or acquired hemostatic defect
   9. Severe renal failure
   10. Severe hepatic failure

4. Reversal of heparin effects
   Minor bleeding
   • Stop heparin
   • Monitor vital signs, aPTT, Hgb, Hct, platelet count.
   Major bleeding
   • Stop heparin
   • Monitor vital signs, aPTT, Hgb, Hct, platelet count.
   • Give blood transfusions as necessary
   • Consider protamine reversal of heparin.
   Protamine
   • Protamine rapidly neutralizes heparin's anticoagulant activity.
   • In the event of a critical bleed, 1mg of protamine will neutralize approximately 100 units of heparin.
   • Protamine can cause severe, anaphylactoid reactions, use only when severe bleeding warrants it.

5. Heparin Induced Thrombocytopenia (HIT)

   HIT is a widely recognized disorder that is observed in 2 to 4% of patients who receive heparin. Heparin-induced thrombocytopenia is a transient hypercoagulable state that occurs as a result of an immune mediated reaction to heparin and involves activation of platelets and massive thrombin generation. HIT appears to be encountered more frequently as use of anticoagulant therapy becomes more widespread. The spectrum of HIT disease ranges from clinically insignificant to severe thrombosis. Overall, thrombosis occurs in approximately 33% of patients diagnosed with HIT and is associated with high morbidity and mortality rates. HIT thrombosis can produce devastating complications, including necrosis of the extremities, stroke, myocardial infarction, and pulmonary embolism.

   Heparin-induced thrombocytopenia is divided into 2 types. Type I is an early-onset, mild decline in platelet count and is reversible. This condition is thought to be caused by the direct platelet-aggregating effect of heparin. In contrast, Type II HIT is an immune-mediated reaction that typically occurs 2 to 5 days after the initial heparin exposure. After re-exposure to heparin, however, patients may develop a rapid onset Type II HIT.

   The diagnosis of HIT is made on the basis of clinical features. HIT should be suspected in any patient who is receiving heparin and has either a low platelet count or one that has decreased 50% from the baseline level. Laboratory tests for heparin-induced thrombocytopenia are now available to confirm the diagnosis.

   Strongly consider HIT when:

   • Platelet count falls within 4 to 14 days after start of heparin or sooner if patient was previously exposed to heparin.
     • > 30 to 50% from baseline and/or
     • <= 150,000
   • New thrombotic event occurs while receiving heparin therapy.
   • Acute systemic reaction within 5 to 30 minutes of heparin bolus:
     • Cardiorespiratory
     • Inflammatory
     • Gastrointestinal
     • Neurologic

   Although HIT typically occurs 4 to 14 days after heparin exposure, it can occur at any time. Thrombosis has been reported within 30 minutes after heparin re-exposure. Thrombosis can occur before the decline in platelet count or even when the platelet count is recovering and rising.

   HIT has several paradoxes:

   • HIT is an anticoagulant-induced thrombosis
   • Despite thrombocytopenia, HIT is a clotting disorder, not a bleeding disorder
   • Platelet transfusions can increase risk of thrombosis.
   • Warfarin is contraindicated as acute monotherapy.
   • Simply stopping heparin may not prevent thrombosis.

   If HIT is suspected, do not switch to a low-molecular-weight heparin, LMWH's will cross-react with the antibody 90% of the time. Currently 2 agents are available to treat HIT:

   • Lepirudin
   • Argatroban

IV. Program procedure

1. Prospective dosing
   The program first asks for a target therapeutic range. The target therapeutic range is used to determine the dosage adjustment guide which is printed on the consult form. Choose to target either 1.5 to 2.5 times the control aPTT or a heparin response curve as determined by the your hospital laboratory.

   If using the first method, the program asks for the initial aPTT, which is either the patient's baseline aPTT (preferred) or, if unavailable, the mean value of the normal range for the aPTT.

   The program calculates Ideal initial loading dose and maintenance doses. The user then enters a practical dose.

2. Evaluation of PTT data
   The program first asks for the target therapeutic range which is used to evaluate the PTT and determine the dosage. Choose to target either 1.5 to 2.5 times the control aPTT or the heparin response curve as determined by your hospital laboratory. If the first method is selected, the program then asks for the initial aPTT (before Heparin), the current aPTT, and the current dose.
   

   The program then calculates an incremental loading dose or time to hold the infusion, if necessary. The user then enters a practical dose.

V. Heparin Dosing Flow Chart

VI. Pharmacokinetic formulas

1. Initial Dosing
   1. Determine dosing weight
      DW = LBW + ((TBW - LBW)/3)
      where TBW = total body weight
      LBW = lean body weight
      

   2. Determine loading dose
      If age < 70 then LD = 80 units x DW
      If age >= 70 then LD = 50 units x DW
      

   3. Determine initial infusion rate
      ko = 18 units/hr x DW
      

   4. Calculate heparin concentration
      
      1. Calculate Vd (blood volume)
         Male: 0.3669 x (Ht)³ + 0.03219 x TBW +0.604
         F: 0.3561 x (Ht)³ + 0.03308 x TBW + 0.1833
         where Ht = height in meters
         TBW= total body weight
         

      2. Calculate elimination rate
         kel = 0.693 x F x F'
         where F = 1.2 if smoker
         and F' = 0.8 if age >= 70
         

      3. Calculate heparin concentration
         Cp = ko / (Vd x kel)
         where ko is heparin infusion rate
         

2. Adjusting maintenance dose
   aPTT ratio
   
   

   aPTT ratio	Loading Dose	Maintenance dose
   Less than 1.2 times control	50 u/kg	Increase by 4 u/kg/hr
   1.2-1.3 times control	25 u/kg	Increase by 3 u/kg/hr
   1.3-1.4 times control	None	Increase by 2 u/kg/hr
   1.5-2.5 times control	None	No change
   2.6-2.9 times control	None	Decrease by 2 u/kg/hr
   3-4 times control	Hold for 1 hour	Decrease by 3 u/kg/hr
   Greater than 4 times control	Hold for 2 hours	Decrease by 4 u/kg/hr

   The control value used to determine the ratio is poorly defined, it may be the mean value of the normal range for the aPTT, or the patient's baseline aPTT (the aPTT measured before any heparin). Use of the patient's baseline as the control has gained popularity based on the fact that many patients undergoing thrombotic episodes have shortened aPTTs.

   aPTT Range (Heparin response curve)
   
   

   aPTT corresponding to	Loading Dose	Maintenance dose
   Less than 0.1 u/ml*	50 u/kg	Increase by 3 u/kg/hr
   0.1-0.15 u/ml*	25 u/kg	Increase by 2 u/kg/hr
   0.16-0.19 u/ml*	None	Increase by 2 u/kg/hr
   0.2-0.4 u/ml*	None	No change
   0.41-0.5 u/ml*	None	Decrease by 2 u/kg/hr
   0.51-0.6 u/ml*	Hold for 1 hour	Decrease by 2 u/kg/hr
   Greater than 0.6 u/ml*	Hold for 2 hours	Decrease by 3 u/kg/hr

   *As determined by local lab. An approximation of the heparin concentration can be made by testing the aPTT reagent in a plasma system that has been calibrated by addition of a range of clinically relevant concentrations of heparin. This heparin response curve can then be entered into the Kinetics program and used as the basis for dosage adjustments (highly recommended).

VII. Bibliography

1. Salzman EW, et al. Management of heparin therapy; a controlled prospective trial. N Engl J Med 1975; 292;1046-50.
2. Glazier RL, Crowell EB. Randomized prospective trial of continuous versus intermittent heparin therapy. JAMA 1976; 12; 1365-67.
3. Chenella FC, et al. Improved method for estimating initial heparin infusion rates. Am J Hosp Pharm 1979; 36;782-84.
4. Greenlaw CW, Henrietta GC, Stolley SN. Standardized heparin dosage schedule using pharmakokinetic principles. Am J Hosp Pharm 1979; 36;920-23.
5. Wilson JR, Lampman J. Heparin therapy: a randomized prospective study. Am Heart J 1979;155-8.
6. Estes, JW. Clinical Pharmacokinetics of Heparin. Clin Pharm 1980 5:204-220.
7. Wilson JE, Bynum LJ, Parkey RW, Heparin therapy in venous thromboembolism; JAMA 1981; 70; 808-16.
8. Self TH, et al. Concurrent initiation of heparin and warfarin therapy. Am Heart J. 1981; 102;470-71.
9. Hattersley PG, et al. Adjusting heparin infusion rates from the initial response to activated coagulation time. DICP 1983;17:632-634.
10. Saya Frank, et al. Pharmacist-directed heparin therapy using a standard dosing and monitoring protocol. Am J Hosp Pharm 1985; 42:1965-1969.
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12. Macleod CM, et al. Comparison of two methods of continuous intravenous heparin therapy. Hosp Pharm 1985; 20;649-54.
13. Hull RD, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. NEJM 1986;18:1109-14.
14. Cipolle RJ, Rodvold KA. "Heparin", in Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics. San Francisco. Applied Therapeutics, 1986; pp 908-943.
15. Rivey MP, Peterson JP. Pharmacy-managed, weight-based heparin protocol. AJHP 1993; 50:pp 279-84.
16. Brill-Edwards P, et al. Establishing a therapeutic range for heparin therapy. Ann Intern MEd 1993; 119:104-109.
17. Raschke RA, et al. The weight-based heparin nomogram compared with a standard care nomogram: a randomized controlled trial Ann Intern Med 1993; 119:874-81
18. Kershaw B, et al. Computer-assisted dosing of heparin: management with a pharmacy-based anticoagulation service. Arch Intern Med 1994;154:10005-1011.
19. Campbell NR, et al. Aging and heparin-related bleeding. Arch Intern Med 1996; 156:857-60.
20. Schlicht JR, et al. Reevaluation of a weight-based heparin dosing nomogram: is institution specific modification necessary? Ann Pharmacother 1997; 31:1454-9.
21. White RH, et al. Effect of weight, sex, age, clinical diagnosis, and thromboplastin reagent on stead-state intravenous heparin requirements. Arch Intern Med 1997;157:2468-2472.
22. Volles DF, et al. Establishing an institution-specific therapeutic range for heparin. AJHP 1998;55:2003-6.
23. Braunwald E, et al. Diagnosing and managing unstable angina, Quick reference quide for clinicians. US Dept of HHS, PHS, AHCPR, NHLBI. 1994, pp 6-7.
24. Brieger DB, Mak KH, Kottke-Marchant K, Topol EJ. Heparin-induced thrombocytopenia. J Am Coll Cardiol 1998; 31:1449–59.

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