Antithrombotic therapy in deep vein thrombosis and pulmonary embolism After 50 years of clinical use anticoagulants are still the mainstay of treatment for venous thromboembolism. Several studies have demonstrated that failure to attain or to maintain an adequate anticoagulant effect with heparin after venous thromboembolism is associated with an increased risk of recurrence. The safety and effectiveness of heparin administered by continuous intravenous infusion has been compared with administration by intermittent intravenous injection; three studies reported less bleeding with the former. The relative efficacy and safety of continuous intravenous and intermittent subcutaneous heparin appear to be comparable. The readily available and relatively inexpensive activated partial thromboplastin time test is used most commonly to monitor heparin therapy. Recent audits indicate that current practices in the administration of heparin are often suboptimal because of an inadequate starting dose, a delay in obtaining or responding to activated partial thromboplastin time test results, or inappropriate adjustments of heparin doses. Attempts have recently been made to improve practices in the administration of heparin by developing a standardization protocol. Recommendations for patient management are discussed. (AM HEART J 1992;123:1115-22.)

Jack Hirsh, MD Hamilton, Ontario, Canada

The objectives of treating patients with venous thromboembolism are to prevent death from pulmonary embolism, to reduce morbidity from the acute event, to minimize postphlebitic symptoms, and to prevent thromboembolic pulmonary hypertension. PREVENTING

DEATH

FROM PULMONARY

EMBOLISM

Good evidence indicates that anticoagulants are effective in reducing mortality from pulmonary embo1ism.l Vena caval interruption, usually with a Greenfield filter, is considered when anticoagulant therapy is contraindicated because of the risk of previous or life-threatening hemorrhage.2 Far less commonly, caval interruption is used when anticoagulant therapy has failed. Thrombolytic therapy with streptokinase, urokinase, or tissue plasminogen activator is more effective than heparin alone in correcting the angiographic defects produced by pulmonary emboli, and may be more effective than heparin in preventing death in patients with shock associated with massive pulmonary embolism.3-5 Thrombolytic therapy is therefore the treatment of choice in patients with massive pulmonary embolism or in those with underlying cardiac or pulmonary disease in whom From the Hamilton Civic Hospitals Division, and McMaster University. Reprint Centre, 4/o/35105

requests: Jack ‘ill Concession

Hirsh, MD, St., Hamilton,

Research Hamilton Ontario,

Centre,

Henderson

General

Civic Hospitals Research Canada L8V lC3.

even a small or moderate embolus may be life threatening. Thromboendarterectomy is effective in selected cases of chronic thromboembolic pulmonary hypertension with proximal pulmonary arterial obstruction.6 Urgent pulmonary embolectomy is usually restricted to patients with massive embolism whose blood pressure cannot be maintained despite thrombolytic therapy and vasopressor agents.7 REDUCING

MORBIDITY

FROM THE ACUTE

EVENT

Although it has never been evaluated by an appropriately designed clinical trial, there is a strong impression that acute symptoms of deep vein thrombosis and pulmonary embolism are improved by heparin treatment. PREVENTING SYNDROME

MORBIDITY

FROM THE POSTPHLEBITIC

In patients treated with heparin and oral anticoagulants, the frequency of postphlebitic syndrome after 2 years ranges from 60% to 70% for patients with proximal vein thrombosis and from 30 % to 40 % for those with calf vein thrombosis.8 Surgical thrombectomy is ineffective in preventing postphlebitic syndrome because most thrombi recur after they are removed.2 The use of thrombolytic therapy to prevent postphlebitic syndrome has been evaluated to a limited extent. Streptokinase treatment produces complete lysis in 30% to 40% of acute venous thrombi and partial lysis in another 30 % .3 In con1115

1116

Hirsh

American

trast, heparin is associated with complete lysis in less than 10% of the patients with acute venous thrombosis.3 Results of a pooled analysis indicate that thrombolysis occurs 3.7 times more often among patients treated with streptokinase than among patients treated with heparin.g Five randomized studies have reported a lower frequency of postphlebitic syndrome in patients treated with streptokinase than in patients treated with heparin.3 One relatively large clinical trial reported no difference in the manifestations of postphlebitic state between the heparin and streptokinase treatment groups after 5 years’ followup. However, patients in this trial were treated for a mean of 9 days after the acute event, and thus might have had irreversible venous valve damage before treatment was begunlo PREVENTION EMBOLISM

OF LATE

EFFECTS

OF PULMONARY

Clinically significant pulmonary hypertension is an uncommon complication of pulmonary embolism. In randomized trials comparing heparin with either streptokinase or urokinase in patients with acute pulmonary embolism, follow-up serial lung scans that were performed 2 weeks, 3 months, and 1 year after treatment demonstrated no apparent difference in the extent of lysis between patients treated with heparin and those treated with thrombolytic agents after the first week of treatment.ll A subsequent study of a subgroup of these patients reported that pulmonary capillary blood volume and pulmonary perfusion were significantly better at 2 weeks and at 1 year in patients treated with fibrinolytic therapy than in patients treated with heparin.i2 The clinical importance of these findings, however, is uncertain. Moser et a1.6have reported their experience with surgical pulmonary endarterectomy in carefully selected patients with chronic thromboembolic pulmonary hypertension. Most patients with obstruction to proximal pulmonary arteries showed impressive improvement after endarterectomy. The authors stress the importance of careful patient selection and the need for expert operative and postoperative management. EVIDENCE FOR EFFECTIVENESS ANTICOAGULANTS

OF

After 50 years of clinical use anticoagulants are still the mainstay of treatment for venous thromboembolism. Early experimental evidence showing that anticoagulants benefit patients with pulmonary embolism came from the landmark study by Barritt and

April 1992 Heart Journal

Jordon.’ The use of anticoagulants in the treatment of venous thromboembolism was then supported by a number of descriptive studies.13 In the last decade well-designed, randomized clinical trials became the accepted standard for making management decisions, and during this time convincing evidence emerged to confirm and extend the effectiveness of anticoagulants in the treatment of venous thromboembolism. Randomized clinical trials performed by Hull et a1.14and Lagerstedt et a1.15established that patients with venous thrombosis who are treated with an initial course of intravenous heparin require continuing anticoagulant therapy for up to 3 months to prevent recurrence. In these two studies patients who were randomized into an inadequate treatment group (5000 IU subcutaneous heparin twice daily)14 and a no treatment group15 had a 29 % to 47 % incidence of recurrence after an initial 5 to 14-day course of intravenous heparin, compared with no recurrences in the groups randomized to receive oral anticoagulants for 3 months. In 1986 Hull et a1.16demonstrated that failure to attain an adequate anticoagulant effect with heparin in patients with proximal vein thrombosis is associated with a high rate of recurrence. In this study 115 patients with proximal vein thrombosis were randomized to receive 30,000 U of heparin either by continuous intravenous infusion or by subcutaneous injection in two divided doses (15,000 U twice daily). Both groups received an initial 5000 U bolus of heparin. Thirty-six of 57 patients (63 % ) randomly assigned to receive subcutaneous heparin had an activated partial thromboplastin time (APTT) at 24 hours that was less than 1.5 control (heparin level 4o The reasons for suboptimal administration of heparin doses include an inadequate starting dose, delay in obtaining or responding to the APTT test result, and inappropriate heparin dosage adjustments. In a recent study Cruickshank et a1.41attempted to improve the practice of administering doses of heparin by developing a standardization protocol. Heparin was administered in an initial dose of 5000 U intravenously as a bolus and then in a dose of 32,000 U/24 hr by continuous infusion. The dosage of heparin was then adjusted by performing an APTT at 6 hours according to a nomogram (Table I). Both the starting dose and the dosage adjustments were selected on the basis of trial and error. The results that were obtained when the APTT test was maintained in the therapeutic range were compared with results obtained at the same hospital with the use of a historic control group; the APTT tests were in the therapeutic range earlier and more frequently when the standardized approach was used (p < 0.05). The initial APTT at 6 hours was below the therapeutic range in 30% of patients, in the therapeutic range in another 30% of patients, and above the therapeutic range in 40% of patients when the standardized starting dose was used. With this information a choice can be made to use a higher starting dose in patients at low risk for bleeding or to use a lower dose in those who are at high risk of bleeding. The nomogram developed for dose adjustment is effective, because the mean time to reach an APTT in therapeutic range was 8.8 hours at an average dose of 33,000 U/24 hr. At 24 hours less than 20% of patients were below the therapeutic range, and 66% were in the

Volume Number

123 4, Part

2

therapeutic range; at 48 hours less than 10% were below the therapeutic range, and 81% were in the therapeutic range. These results were significantly better than results for the control group. The mean dose of heparin administered by continuous intravenous infusion that is required to prolong the APTT to 1.5 times control (heparin level 0.2 to 0.4 U/ml) is approximately 33,000 U/24 hr.41 The mean dose is about 10% higher if it is administered by subcutaneous injection. Approximately 20% of patients require doses of heparin greater than 35,000 U/24 hr to prolong the postheparin APTT result to 1.5 to 2 times the normal mean result. These patients are often considered to be resistant to heparin. Heparin resistance is a term used to describe patients whose laboratory test result response to heparin is atypically poor. It may be caused either by disassociation of the APTT from the heparin level or by true heparin resistance. Dissociation of the APTT from the heparin level. These patients have therapeutic heparin levels asmeasured by the anti-Xa heparin assay or by the anti-IIa heparin assay, but have a poor response as measured by the APTT test. This phenomenon is typically seen in the latter stages of pregnancy and occurs in approximately 50 % of all patients who require large doses of heparin to prolong their APTT. Many of these patients have a very short pretreatment APTT, which may be caused by high concentrations of procoagulants. These patients are identified as having a poor APTT response but an adequate heparin level. True heparin resistance. Patients may fail to show an elevation of both the APTT and the circulating heparin level despite treatment with high doses of heparin. This form of heparin resistance can occur in the early stagesof treatment of pulmonary embolism when heparin clearance is accelerated, or less commonly if the patient’s blood contains inadequate levels of heparin cofactor activity. The dose of heparin should be increased and the patient’s blood tested for antithrombin III (ATIII) deficiency. Heparin therapy results in a moderate decrease in AT111 levels, but this reduction is unlikely to be clinically important in patients whose AT111 levels are within the normal range before beginning heparin therapy.42 It could, however, produce heparin resistance in patients who are congenitally ATIII deficient. However, even ATIII-deficient patients may respond normally to heparin in terms of both their postheparin APTT test result and their heparin levels.43 On the basis of current evidence heparin therapy can be monitored either by the heparin level or by global tests, such as the APTT. If the heparin level is used it should be maintained between 0.2 and 0.4

Deep vein thrombosis and pulmonary embolism

1 I 19

U/ml (on the basis of protamine titration) or between 0.3 and 0.7 U/ml on the basis of the anti-factor Xa assay. If the APTT test is used, it should be adjusted to a ratio equivalent to a heparin level of 0.2 to 0.4 U/ml on the basis of protamine titration, which for many thromboplastins corresponds to a ratio of 1.5 to 2.0 of the mean of the normal laboratory control. DURATION

OF HEPARIN

ADMINISTRATION

Current practice dictates that patients with venous thromboembolism should be admitted to the hospital and treated with intravenous heparin for several days. Many of these patients can be discharged from the hospital after 2 or 3 days if the duration of heparin treatment is reduced or if they will be treated by the subcutaneous route at home. Early experimental studies with animals suggested that heparin is a more effective antithrombotic agent than vitamin K antagonists in experimental venous thromboembolism and that the optimal antithrombotic effects of vitamin K antagonists are delayed for 6 days. 44,45 Because of these considerations it has been common practice to treat patients who have venous thromboembolism with heparin for a period of 7 to 10 days, to start oral anticoagulants after 3 to 5 days, and to overlap both anticoagulants for 4 to 5 days. This approach has recently been challenged by the results of two studies.31>46One study demonstrated that 9 days of heparin therapy was not superior to 4 days of heparin with overlapping warfarin.46 The other study showed that 10 days of heparin therapy was not superior to 5 days of heparin with overlapping warfarin. 31In both studies warfarin was begun within the first 24 hours in patients randomized to receive the short course. THE NEED FOR LONG-TERM ANTICOAGULANT THERAPY AFTER AN INITIAL COURSE OF HEPARIN

A retrospective survey by Coon and Willis47 provided evidence that the frequency of clinically diagnosed recurrent venous thrombosis was lower in patients who were treated with oral anticoagulants after they were discharged from the hospital than in a group that did not receive long-term anticoagulant therapy. This study, which formed the basis for continuing anticoagulant therapy after discharge from the hospital, was retrospective and used clinical features only for the initial diagnosis and for the diagnosis of recurrent thromboembolism. The studies by Hull et a1.14and Lagerstadt et a1.15 provided definitive evidence that patients with deepvein thrombosis who are treated with an initial course of heparin therapy have a very high rate of recurrence unless effective anticoagulant therapy is continued

1120 Table APTT (see) 550 50-59 60-85 86-95 96-120 >120 *Heparin

Hirsh

American

II. Intravenous heparin dose-titration nomogram* Bolus (U

Hold (Min)

5000 0 0 0 0 0 concentration

Change in rate of infusion

0 0 0 0 30 60

f3 +3 0 -2 -2 -4

Repeat APTT 4 Hr 6 Hr Next Next 6 Hr 4 Hr

day day

20,000 U in 500 ml.

for weeks or months after they are discharged from the hospital. The study by Hull et a1.i4 was the first of three randomized clinical trials that evaluated the need for long-term treatment of patients with acute venous thrombosis.14~48~ 4gThe first study showed that fulldose, oral anticoagulant therapy is much more effective than low-dose subcutaneous heparin in preventing recurrent venous thromboembolic events, but that it is associated with a high rate of clinically overt bleeding.14 The second study showed that subcutaneous heparin, when adjusted to maintain the midinterval APTT determined 6 hours after injection at 1.5 times the control value (equivalent to a heparin level by protamine neutralization of 0.2 to 0.4 U/ml), is as effective as full-dose oral anticoagulants in preventing recurrent venous thromboembolism. The study also showed that adjusted-dose subcutaneous heparin is associated with a significantly lower incidence of bleeding than sodium warfarin.48 Finally, the third study demonstrated that a less intense warfarin regimen (targeted therapeutic range international normalized ratio [INR] of 2.0; prothrombin time [PT] 1.3) is as effective in preventing recurrent venous thrombosis, but is associated with a lower risk of bleeding than the standard full-dose warfarin regimen (INR = 3.5 to 5.0; PT = 1.6 to 2.0).4g THE NEED TO TREAT

CALF-VEIN

THROMBOSIS

Between 20 % and 30 % of calf-vein thrombi extend into the proximal venous segment if left untreated.50-51The proponents of nontreatment of calf-vein thrombosis recommend that patients with clinically suspected venous thrombosis should be investigated by noninvasive tests such as impedance plethysmography, B-mode imaging, or Doppler ultrasonography, which are sensitive to proximal (popliteal, femoral, or iliac) vein thrombosis but are insensitive to calf-vein thrombosis.51 The safety of this approach has been tested in four large studies of patients with clinically

April 1992 Heart Journal

suspected venous thrombosis who were followed by serial impedance plethysmography.“l-s4 These studies demonstrated that calf-vein thrombi are rarely associated with clinically significant pulmonary embolism, provided that proximal extension is detected by serial impedance plethysmography and treated promptly. On the other hand, good evidence now indicates that extension of calf-vein thrombosis can be prevented if anticoagulants are administered.15 A review of seven studies that have addressed the issue of management of calf-vein thrombosis reveals a consistent message.14,15,50-54Untreated or inadequately treated calf-vein thrombosis has a 20% to 30% risk of extension that can be readily and safely detected by serial impedance plethysmography.4g-5” Symptomatic calf-vein thrombi that extend usually do so in the first 5 days of their appearance, and extension or recurrence of untreated calf-vein thrombosis is rare after the first week in which they appear. 4g,52*53 Treatment with intermittent, intravenous heparin for 5 days does not eliminate extension, but it appears to delay this complication until after anticoagulant therapy has been discontinued.ls Treatment of calf-vein thrombosis with anticoagulants for 6 to 12 weeks virtually eliminates clinically important extension and is recommended unless facilities to monitor extension are available.14. l5 In institutions that have the proper facilities to monitor patients for extension, the potential benefits of treating patients who have calf-vein thrombosis that may extend should be weighed against the risks and cost of anticoagulant therapy for the much larger group of patients whose thrombi will not extend. PRACTICAL CONSIDERATIONS: USE OF ANTICOAGULANTS Commencing heparin. Heparin, 5000 U intravenous

as a bolus, is followed by 32,000 U intravenous over 24 hours by continuous infusion, or heparin, 5000 U intravenous as a bolus, is followed by 20,000 U subcutaneous 12 hourly. The APTT test should be performed 6 hours after the bolus or subcutaneous injection, and the heparin dose should be adjusted according to the nomogram (Table II). The APTT test should be repeated daily and adjusted according to the nomogram. Warfarin should be started with a dose of 10 mg daily beginning 24 hours after heparin is started. The PT test should be performed at 48 hours and then daily. The dose of warfarin should be adjusted to obtain an INR of 2.0 to 3.0 (PT ratio of 1.3 to 1.5 using thromboplastin with an International Sensitivity Index of 2.0 to 2.4). The heparin should be

Volume Number

123 4, Part 2

Deep vein thrombosis

discontinued after 5 to 7 days, provided that the PT ratio is in the therapeutic range. Warfarin therapy should be continued for 3 months; the effect of warfarin should be monitored by the PT three times in the first week, then twice weekly for at least 2 weeks or until the dose response is stable, and then weekly thereafter. MANAGEMENT OF PATIENTS VENOUS THROMBOEMBOLISM ANTICOAGULANT THERAPY

WHO HAVE RECURRENT DURING

Recurrent venous thrombosis that occurs during adequate anticoagulant therapy is uncommon. If recurrence occurs in patients whose anticoagulant effect is subtherapeutic, the dose of anticoagulants should be increased and their coagulation test (APTT or PT) monitored frequently. If recurrence occurs in patients whose anticoagulant effect is therapeutic, then either the anticoagulant dose should be increased or a caval filter should be inserted while the patient is maintained at a slightly higher therapeutic range. It is very important to confirm a clinical suspicion of recurrence with appropriate objective tests before concluding that the new symptoms have been caused by recurrent venous thromboembolism. Some patients who develop recurrence during warfarin therapy at an INR of 2.0 to 3.0 respond to a higher dose of warfarin (INR 3.0 to 4.5), whereas others will respond only to subcutaneous heparin, 12 hourly, adjusted to maintain the APTTat 6 hours at 1.5 to 2.0 control. Because long-term heparin therapy may be complicated by osteoporosis, any trial of heparin treatment should be limited to 2 or 3 months, and warfarin treatment should then be restarted. Patients who develop recurrent venous thromboembolism while being treated with anticoagulants should probably be treated with anticoagulants indefinitely, unless a specific cause of recurrence can be identified and reversed. MANAGEMENT RECURRENCE STOPPED

OF PATIENTS WHO DEVELOP WHEN ANTICOAGULANT THERAPY

IS

Patients who develop recurrent venous thrombosis without provocation after a 3-month course of adequate anticoagulant therapy have a high risk of recurrence unless their recurrent episode is treated with warfarin on a long-term basis. Our approach has been to treat the first recurrence with a 12-month course of anticoagulants and to treat subsequent recurrences with anticoagulants for an indefinite period of time.

and pulmonary

embolism

I I2I

INDICATIONS FOR INDEFINITE ANTICOAGULANT THERAPY FOR VENOUS THROMBOEMBOLISM

Anticoagulant therapy is continued indefinitely in (1) patients who have had more than one recurrent episode of venous thromboembolism; (2) patients with venous thromboembolism who have a continuing risk factor such as a deficiency of ATIII, protein C, or protein S, a circulating antiphospholipid antibody, or malignant disease; and (3) patients with thromboembolic pulmonary hypertension. REFERENCES 1. Barritt

2. 3.

4.

5.

6.

7.

8.

9.

10.

11. 12.

13. 14.

15.

16.

17.

DW, Jordon SC. Anticoagulant drugs in the treatment of pulmonary embolism: acontrolled trial. Lancet 1960;1:130912. Coon WW. Operative therapy of venous thromboembolism. Mod Concepts Cardiovasc Dis 1974;43:71-5. Marder VJ, Bell WR, Victor J. Fibrinolytic therapy. The agents and their mode of actions. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis. 2nd ed. Philadelphia: JB Lippincott Co, 1987:1393-437. Tibbutt DA. Davies JA. Anderson JA, et al. Comparison bv controlled clinical trial of streptokinase and heparm in treatment of life-threatening pulmonary embolism. Br Med J 1974;1:343-7. Miller GAH, Sutton GC, Kerr IH, et al. Comparison of streptokinase and heparin in the treatment of isolated acute massive pulmonary embolism. Br Med J 1971;2:681-4. Moser KM, Spragg RG, Utley J, et al. Chronic thrombotic obstruction in major pulmonary arteries. Results of thromboendarterectomy in 15 patients. Ann Intern Med 1983;99:299-304. Miller GAH, Hall RJC, Paneth M. Pulmonary embolectomy, heparin and streptokinase: their place in the treatment of acute massive pulmonary embolism. AM HEART J 1977; 93:568-74. Porter J, Seaman AJ, Common HC, et al. Comparison of heparin and streptokinase in the treatment of venous thrombosis. Am Surg 1975;41:511-9. Goldhaber SZ, Buring JE, Lipnick RJ, et al. Pooled analysis of randomized trials of streptokinase and heparin in phlebographically documented acute deep vein thrombosis. Am J Med 1984;76:393-7. Kakkar VV, Lawrence D, Fok J, Djazaeri B. Objective assessment of late results of treatment of deep vein thrombosis [Abstract]. Br J Surg 1981;68:807. Urokinase Streptokinase Embolism Trial. Phase II results: a cooperative study. JAMA 1974;229:1606-13. Sharma CRK. Burleson VA. Sasahara AA. et al. Effect of thrombolytic therapy on pulmonary capillary blood volume in patients with pulmonary embolism. N Engl J Med 1980;303:842-5. Kanis JA. Heparin in the treatment of pulmonary thromboembolism. Thromb Diath Haemorrh 1974;32:519:27. Hull R, Delmore T. Genton E. et al. Warfarin sodium versus low-dose heparin inthe long-term treatment of venous thrombosis. N Engl J Med 1979;301:855-8. Lagerstedt CI, Fagher BO, Albrechtsson U, Olsson CG, Oqvist KBW. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985;i:515-8. Hull RD. Raskob GE. Hirsh J. et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-14. Glazier RL, Crowell EB. Randomized prospective trial of continuous or intermittent heparin therapy. JAMA 1976;236: 1365-7.

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EW, Deykin D, Shapiro RM, Rosenberg R. Manage18. Salzman ment of heparin therapy. N Engl J Med 1975;292:1046-50. MJ, O’Brien BD, Thong KL, et al. Hemorrhagic 19. Mant complications of heparin therapy. Lancet 1977;i:1133-5. 20. Wilson JR, Lampman J. Heparin therapy: a randomized prospective study. AM HEART J 1979;97:155-8. 21. Doyle DJ, Turpie AGG, Hirsh J, et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med 1987;107:441-5. PG, Kakkar VV, Scully MF, et al. An objective study 22. Bentley of alternative methods of heparin administration. Thromb Res 1980;18:177-88. G, Fagrell B, Holmgren K, et al. Subcutaneous ad23. Andersson ministration of heparin: a randomized comparison with intravenous administration of heparin to patients with deep vein thrombosis. Thromb Res 1982;27:631-9. MG, Shaw JW, Thomson GJL, Cumming JGR, Tho24. Walker mas ML. Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomized trial. Br J Med 1987;294:1189-92. kinetics in 25. Hirsh J. van Aken WG. Gallus AS. et al. Henarin venous thrombosis and pulmonary embolism. Circulation 1976;53:691-5. C, Gabaig AM, Dupouy D, Sie P. Evidence 26. Boneu B, Caranobe for a saturable mechanism of disappearance of standard heparin in rabbits. Thromb Res 1987;46:835-44. 27. de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982;60:1251-8. 28. O’Sullivan EF, Hirsh J, McCarthy RA, DeGruchy GC. Heparin in the treatment of venous thromboembolic disease: administration, control and results. Med J Aust 196&2:153-g. 29. Basu D, Gallus A, Hirsh J, Cade JF. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972;287: 324-7. 30. Hirsh J, O’Sullivan EF, Gallus AS, Martin M. Evaluation of subcutaneous calcium heparin therapy in the treatment of thromboembolic disease. Med J Aust 1970;1:15-7. 31. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990;322:1260-4. B, Hartmann, et al. Heparin treatment 32. Holm HA, Finnanger of deep venous thrombosis in 280 patients: symptoms reduced to dosage. Acta Med Stand 1984;215:47-53. E, Gent M. Relation33. Chiu HM, Hirsh J, Yung WL, Rogoeczi ship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood 1977; 4917184. of action and monitoring of anticoagu34. Hirsh J. Mechanism lants. Semin Thromb Hemost 1986;12:1-11. 35. Levine MN, Hirsh J. Hemorrhagic complications of anticoagulant therapy. Semin Thromb Hemost 1986;12:39-57. 36. The urokinase pulmonary embolism trial: a national cooperative study. Circulation 1973;47(suppl):l-100.

American

April 1992 Heart Journal

37. Laudefeld CS, Cook EF, Flatley M, et al. Identification and preliminary validation of predictors of major bleeding in hosoitalized uatients starting anticoagulant therapy. Am J Med i987;82:703-13. EW. Devkin D. Maver Shaniro R. Rosenberg RD. 38. Salzman Management’of heparin therapy: controlled prospectivetrial. N Engl J Med 1975;292:1046-50. 39 Wheeler A, Jaquiss R, Newman J. Physician practices in the treatment of pulmonary embolism and deep vein thrombosis. Arch Intern Med 1988,148:1321-5. 40 Fennerty A, Thomas P, Backhouse G, et al. Audit of control of heparin treatment. Br Med J 1985;290:27-8. 41 Cruickshank MK, Levine MN, Hirsh J, Roberts RS, Siquenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-7. 42. Gallus AS, Goodall KT, Tillett J, Jackaman J, Wycherley A. The relative contributions of antithrombin III during heparin treatment, and of clinically recognizable risk factors, to early recurrence of venous thromboembolism. Thromb Res 1987; 46:539-53. P. Manage43. Leclerc JR, Hirsh J, Geert W, Panju A, Nguyen ment of anti-thrombin III deficiency during pregnancy without administration of anti-thrombin III. Thromb Res 1986; 41:567-73. management of venous thrombosis. Ann 44. Wessler S. Medical Rev Med 1986;27:313-9. 45. Wessler S, Gitel SN, Bank H, Martinowitz U, Stephenson RC. An assay of antithrombotic action of warfarin: its correlation with the inhibition of stasis thrombosis in rabbits. Thromb Haemost 1979;40:486-98. 46. Gallus A, Jackman J, Mills W, Tillett J, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986;6:1293-6. 47. Coon WW, Willis PW. Recurrence of venous thromboembolism. Surgery 1973;73:823-7. 48. Hull RD, Delmore T, Carter C, et al. Adjusted subcutaneous heparin vs warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982;306:189-94. 49. Hull RD, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307:1676-81. 50. Kakkar VV, Flanc C, Howe CT, et al. Natural history of postoperative vein thrombosis. Lancet 1969;2:230-2. 51. Hull RD, Hirsh J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis: a randomized trial. Ann Intern Med 1985;102: 21-8. 52. Wheeler HB, Anderson FA Jr. Can noninvasive tests be used as the basis for treatment of deep vein thrombosis? In: Bernstein EF, ed. Noninvasive diagnostic techniques in vascular disease. St. Louis: The CV M&by Co, 1982:545-59. 53. Huisman MV. Buller HR. ten Cate JW. Vreeken J. Serial impedance plethysmography for suspected deep venous thrombosis in outpatient; N Engl J Med 1986;314:823. 54. Jonker JJC. de Boer AC. den Ottolander GJH. Imaedance Alethysmography in the management of patients with deep vein thrombosis at home [Abstract]. Thromb Haemost 1985;54:99.