619
VIEWPOINT Setting the record straight on low-dose heparin As a general surgeon with a heart disorder but limited knowledge of cardiology, I have tried to learn more about the current treatment of atherosclerosis. 12 My efforts revealed numerous publications on heparin-more specifically, on low-dose regimens of the drug and its many actions other than anticoagulation.3,4 Clinical trials to evaluate these actions have been hampered by widely prevalent concerns about its complications: bleeding, osteoporosis, and thrombocytopenia. Such worries are valid for standard-dose heparin but do not apply to low-dose regimens. Few of the dozens of internist colleagues I have questioned understand how heparin acts in low doses. Most believe that preoperative low-dose regimens of heparin help prevent deep vein thrombosis by an anticoagulant effect. That concept is incorrect since an injection of a low-dose of heparin rarely prolongs the activated partial thromboplastin time (APTT). If it were otherwise, subsequent surgery would result in uncontrollable haemorrhage. The concept has remained unchallenged for more than two decades after
it was shown to be erroneous. None of the current editions of six popular standard textbooks of medicine, physiology, and haematology that I consulted explained correctly how heparin in low dose prevents postoperative deep vein thrombosis.5-11 Standard doses of heparin usually vary between 25 000 and 60 000 units daily, whereas for low-dose regimens 15 000 or less (commonly 5000 to 10 000) units are given daily.’1 Standard-dose heparin is usually given intravenously, first as a 5000 unit bolus, followed by an infusion at 700-2000 units per hour. The amount of heparin circulating is sufficient to lengthen the clotting time by increasing the rate at which anti-thrombin III removes thrombin and factors IX, X, XI, and XII. Even after uptake of heparin by the endothelium, sufficient remains in the circulation to maintain APTT at 1-5 to 2 times normal (usually 50-70 s). Sometimes standard-dose heparin is given as subcutaneous injections of 7500-15 000 units every 12 h to maintain APTT as above. These dosages are indicated when an anticoagulant state is desired for such specific indications as the treatment of existing deep vein thrombosis, pulmonary embolism, and coronary thrombosis. The anticoagulant state continues as long as a sufficiently large amount of heparin remains in the blood stream, and long-term administration at standard doses may result in excessive bleeding. With low-dose heparin most of the already small amount of heparin would have relocated and adhered to or entered the endothelial linings of blood vessels a few minutes after injection. There heparin reinforces the normal anti-thrombotic action of endogenous heparin activity on the endothelial surfaces, thereby protecting against deep-vein thrombosis.3 So little heparin remains in the circulation that clotting remains normal and the risk of bleeding is very slight. Hence surgery can be safe, and many authors have reported patients who have received low doses of heparin daily ADDRESS: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, CA 90048, USA (A G Shulman, FAGS). Correpondence to 9201 Sunset Boulevard, Los Angeles, California, CA 90069, USA.
for months and even years with excessive bleeding.12,13
an
insignificant incidence of
That circulating heparin is taken up by vascular endothelium was first suspected by Samuels and Webster in 1952.14 Histological proof was provided by Zugibe15 and by Hiebert and Jaques.16 After a subcutaneous injection of a standard dose of heparin, the concentration of the drug in the target organ-namely, vascular endothelium-is often 1000 or more times that in the blood.l’ Haim and Des Prez, in a review article on pulmonary embolism, have concluded that "bleeding complications of low-dose heparin are generally reported as low and mostly confined to patients who have received other drugs with anticoagulant activity, notably aspirin, or had underlying subclinical bleeding disorders" .18 Levine and Hirsh, in a review of 15 studies on the use of low-dose heparin, concluded that the weight of evidence suggests that the risk of haemorrhage with its use is small.19 It is comforting in today’s litigious atmosphere to note that the product information pamphlet that accompanies each batch of heparin states: "There is usually no need to monitor coagulation parameters in patients receiving low-dose
heparin".2o Surgeons have been heard to complain that "It was that damned heparin that did it" when confronted with unexpected bleeding. However, controlled studies have revealed that this same blame is made whether the patient had received heparin or not.21 Few drugs in the pharmacopeia have been so maligned as heparin given in low doses-on the basis of guilt by association resulting from the problems encountered with standard-dose heparin. By this same logic the ingestion of one aspirin tablet would be contraindicated because taking fifty at a time might prove fatal-an obvious absurdity. Another barrier to further investigation of the regimen has been resistance of patients in accepting repeated painful subcutaneous injections. Intrapulmonary heparin is a simple mode of administration and safe;22-24 and recent animal studies have suggested that, contrary to earlier thinking, oral heparin may prove to be an effective, more practical route of delivery.25 Since the benefits of low doses of heparin in the prevention of deep vein thrombosis outweigh the very slight risk of bleeding,26 further investigation of low-dose regimens to evaluate some of heparin’s other potential benefits (eg, reduction of blood lipoprotein by enhancing lipoprotein lipase)" need not be restricted because of an exaggerated concern over the risk of abnormal bleeding. REFERENCES 1. Shulman AG. Heparin for prevention of atherosclerosis. N Engl J Med 1988; 319: 1154-55. 2. Shulman AG. Heparin and atherosclerosis: an investigative report on the treatment of atherosclerosis. Biomed Pharmacother 1990; 44: 303-06. 3. Jaques LB. Heparins—anionic polyelectrolyte drugs. Pharmacol Rev 1979; 31: 99-166. 4. Engelberg H. Heparin and the prevention of atherosclerosis. New York: Wiley-Liss Inc. 1990. 5. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990. 6. Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991.
620
Wyngaarden JB, Smith LH, eds. Cecil textbook of medicine. 18th ed. Philadelphia: WB Saunders, 1988. 8. West J, ed. Best and Taylor physiological basis of medical practice. 11th 7.
ed. Baltimore: Williams and Wilkins, 1985.
Guyton AC. Textbook of medical physiology. 7th ed. Philadelphia: WB Saunders, 1986. 10. Williams WJ, Beutler E, Ersler AJ, Lichtman MA, eds. Hematology. 4th 9.
ed. New York: McGraw-Hill, 1990.
Majerus PW, Broze CG Jr, Miletech JP, Tollefson DM. Anticoagulant, thrombolytic and antiplatelet drugs. Cited in Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990. 12. Sayen JJ, Singer RB, Pierce G, Horwitz O. Unstable angina, myocardial infarction, heparin and death: medium dose heparin (not exceeding 20 000 units/day) in the treatment of patients with acute coronary event—first year and long term comparative mortality. Trans Am Clin Climatol Assoc 1982; 94: 141-53. 13. Neri Serneri GG, Rovelli F, Gensini GF, Pirelli S, Camovali M, Fortini A. Effectiveness of low-dose heparin in prevention of myocardial reinfarction. Lancet 1987; 1: 937-42. 14. Samuels PH, Webster DR. The role of venous endothelium in the inception of thrombosis. Ann Surg 1952; 136: 422-38. 15. Zugibe FT. Mucopolysaccharides of the arterial wall. J Histochem Cytochem 1963; 11: 35-39. 16. Hiebert LM, Jaques LB. Heparin update on endothelium. Artery 1976; 11.
2: 26-37.
17. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976; 8: 195-204. 18. Heim CR, Des Prez R. Pulmonary embolism: a review. Adv Intern Med 1986; 31: 181-212. 19. Levine MN, Hirsh J. Hemorrhagic complications of anticoagulant therapy. Semin Thromb Hemost 1986; 12: 39-57. 20. Manufacturer’s product information package circular on heparin sodium USP injection. Kalamazoo: Upjohn. Revised May 1989. 21. Kakkar W. Low-dose heparin in the prevention of venous thromboembolism. In: Bradshaw RA, Wessler S, eds. Heparin: structure, function and clinical implications. New York: Plenum Press, 1974: 323-40. 22. Bick RL, Ross ES. Clinical use of intrapulmonary heparin. Semin Thromb Hemost 1985; 11: 213-17. 23. Hellgren M, Hagnevik K, Blomback M. Heparin aerosol—effect on blood coagulation and pulmonary function. Thromb Res 1981; 21: 493-502. 24. Kanabrocki EL, Sothem RB, Olwin JH, et al. Intrapulmonary administration of heparin in the morning and its effect upon blood variables. In: Reinberg A, Smolensky M, Labrecque G., eds. Annual reviews in chronopharmacology, vol 7. New York: Pergamon Press, 1990: 169-72. 25. Jaques LB, Wice SH, Hiebert LM. Evidence from endothelium of the gastric absorption of heparin and of dextran sulfates 8000. J Lab Clin Med 1991; 117: 122-30. 26. Consensus conference: prevention of venous thrombosis and pulmonary embolism. JAMA 1986; 256: 744-49.
BOOKSHELF Medical
Management of
Breast Cancer
Edited by Trevor J. Powles and Ian E. Smith. London: Martin Dunitz. 1991. Pp 345. 49.95/$110. ISBN 1-853170755.
Powles and Smith’s book opens with the potentially controversial statement that "Breast cancer is more of a medical than a surgical problem". But medical interventions probably do have most scope for further improvement in breast cancer prognosis and patients’ quality of life. The international array of authors assembled here shows a good balance between contributors from North America, the UK, and mainland Europe. Indeed, balance is the strength of this book: contentious areas are highlighted - and well discussed throughout, but the authors are also allowed to present their own views and assessment of published evidence on medical management of patients with breast cancer; where they might take up a controversial viewpoint the editors provide cross-references to conflicting opinions. There have been many recent advances in our knowledge of the biology of breast cancer, and growth factors, endocrinology, osteolysis, and systemic therapy are reviewed succinctly. There are up-to-date discussions of all the major endocrine therapies, with some of the new aromatase inhibitors and LHRH analogues included; chemotherapy is well covered, and the debates about dose intensification and high-dose chemotherapy for recurrent disease are analysed, as are novel agents. A vital consideration, often overlooked, is the patient’s quality of life during chemotherapy and the improvements that might occur with response to treatment, highlighted here in a chapter by Coates. Henderson and colleagues review recent advances in adjuvant therapy, and a good attempt is made to interpret these results in the light of our knowledge of the underlying biological processes: this helpful analysis should provide a sound basis for the design of future studies. Researchers with experience of primary medical treatment before surgery (neoadjuvant therapy) present their data, and chemoprevention of breast cancer in high-risk patients is well discussed.
Unfortunately, most patients with breast cancer will, if it recurs, eventually die from their disease, but much can be done to improve their quality of life and control their symptoms; there is an excellent section on palliative medicine, symptom control, and management of various common problems. Local recurrence after combined firstline treatment (eg, surgery and radiotherapy with or without chemotherapy or hormone treatment) is perhaps one topic that merits more discussion than it receives here; increased use of adjuvant therapies is likely to make the choice of treatment more
difficult.
Authors and editors have done their tasks well. Medical Management of Breast Cancer is very well laid out and includes references from 1990; each chapter is about 10 pages long-succinct, up to date, and clear. Any physician who looks after patients with breast cancer will enjoy this book, and it can be strongly recommended to trainee oncologists as a concise and readable review of many areas of clinical research interest. Nurses will also find much of value. The high quality of individual chapters and the large amount of information conveyed so painlessly makes the price seem very reasonable. ICRF Clinical Oncology Unit, University of Oxford, Oxford OX3 7LJ, UK
The
ADRIAN L. HARRIS
Psychoses of Epilepsy
Michael R. Trimble. New York: Raven. 1991. $77.50/45. ISBN 0-881677396.
Pp
210.
Trimble has a particular gift for books of this sort: he can be didactic but not pedantic, meticulous without being obsessional, and broad but not over-inclusive. As a result, The Psychoses of Epilepsy can be read with interest by students or postgraduates in any relevant discipline. He sets out a helpful historical background, justifies and explains the process of classification in epileptology and psychiatry, and provides an anatomical and physiological update from which base to launch his exposition on the psychoses.
VIEWPOINT Setting the record straight on low-dose heparin As a general surgeon with a heart disorder but limited knowledge of cardiology, I have tried to learn more about the current treatment of atherosclerosis. 12 My efforts revealed numerous publications on heparin-more specifically, on low-dose regimens of the drug and its many actions other than anticoagulation.3,4 Clinical trials to evaluate these actions have been hampered by widely prevalent concerns about its complications: bleeding, osteoporosis, and thrombocytopenia. Such worries are valid for standard-dose heparin but do not apply to low-dose regimens. Few of the dozens of internist colleagues I have questioned understand how heparin acts in low doses. Most believe that preoperative low-dose regimens of heparin help prevent deep vein thrombosis by an anticoagulant effect. That concept is incorrect since an injection of a low-dose of heparin rarely prolongs the activated partial thromboplastin time (APTT). If it were otherwise, subsequent surgery would result in uncontrollable haemorrhage. The concept has remained unchallenged for more than two decades after
it was shown to be erroneous. None of the current editions of six popular standard textbooks of medicine, physiology, and haematology that I consulted explained correctly how heparin in low dose prevents postoperative deep vein thrombosis.5-11 Standard doses of heparin usually vary between 25 000 and 60 000 units daily, whereas for low-dose regimens 15 000 or less (commonly 5000 to 10 000) units are given daily.’1 Standard-dose heparin is usually given intravenously, first as a 5000 unit bolus, followed by an infusion at 700-2000 units per hour. The amount of heparin circulating is sufficient to lengthen the clotting time by increasing the rate at which anti-thrombin III removes thrombin and factors IX, X, XI, and XII. Even after uptake of heparin by the endothelium, sufficient remains in the circulation to maintain APTT at 1-5 to 2 times normal (usually 50-70 s). Sometimes standard-dose heparin is given as subcutaneous injections of 7500-15 000 units every 12 h to maintain APTT as above. These dosages are indicated when an anticoagulant state is desired for such specific indications as the treatment of existing deep vein thrombosis, pulmonary embolism, and coronary thrombosis. The anticoagulant state continues as long as a sufficiently large amount of heparin remains in the blood stream, and long-term administration at standard doses may result in excessive bleeding. With low-dose heparin most of the already small amount of heparin would have relocated and adhered to or entered the endothelial linings of blood vessels a few minutes after injection. There heparin reinforces the normal anti-thrombotic action of endogenous heparin activity on the endothelial surfaces, thereby protecting against deep-vein thrombosis.3 So little heparin remains in the circulation that clotting remains normal and the risk of bleeding is very slight. Hence surgery can be safe, and many authors have reported patients who have received low doses of heparin daily ADDRESS: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, CA 90048, USA (A G Shulman, FAGS). Correpondence to 9201 Sunset Boulevard, Los Angeles, California, CA 90069, USA.
for months and even years with excessive bleeding.12,13
an
insignificant incidence of
That circulating heparin is taken up by vascular endothelium was first suspected by Samuels and Webster in 1952.14 Histological proof was provided by Zugibe15 and by Hiebert and Jaques.16 After a subcutaneous injection of a standard dose of heparin, the concentration of the drug in the target organ-namely, vascular endothelium-is often 1000 or more times that in the blood.l’ Haim and Des Prez, in a review article on pulmonary embolism, have concluded that "bleeding complications of low-dose heparin are generally reported as low and mostly confined to patients who have received other drugs with anticoagulant activity, notably aspirin, or had underlying subclinical bleeding disorders" .18 Levine and Hirsh, in a review of 15 studies on the use of low-dose heparin, concluded that the weight of evidence suggests that the risk of haemorrhage with its use is small.19 It is comforting in today’s litigious atmosphere to note that the product information pamphlet that accompanies each batch of heparin states: "There is usually no need to monitor coagulation parameters in patients receiving low-dose
heparin".2o Surgeons have been heard to complain that "It was that damned heparin that did it" when confronted with unexpected bleeding. However, controlled studies have revealed that this same blame is made whether the patient had received heparin or not.21 Few drugs in the pharmacopeia have been so maligned as heparin given in low doses-on the basis of guilt by association resulting from the problems encountered with standard-dose heparin. By this same logic the ingestion of one aspirin tablet would be contraindicated because taking fifty at a time might prove fatal-an obvious absurdity. Another barrier to further investigation of the regimen has been resistance of patients in accepting repeated painful subcutaneous injections. Intrapulmonary heparin is a simple mode of administration and safe;22-24 and recent animal studies have suggested that, contrary to earlier thinking, oral heparin may prove to be an effective, more practical route of delivery.25 Since the benefits of low doses of heparin in the prevention of deep vein thrombosis outweigh the very slight risk of bleeding,26 further investigation of low-dose regimens to evaluate some of heparin’s other potential benefits (eg, reduction of blood lipoprotein by enhancing lipoprotein lipase)" need not be restricted because of an exaggerated concern over the risk of abnormal bleeding. REFERENCES 1. Shulman AG. Heparin for prevention of atherosclerosis. N Engl J Med 1988; 319: 1154-55. 2. Shulman AG. Heparin and atherosclerosis: an investigative report on the treatment of atherosclerosis. Biomed Pharmacother 1990; 44: 303-06. 3. Jaques LB. Heparins—anionic polyelectrolyte drugs. Pharmacol Rev 1979; 31: 99-166. 4. Engelberg H. Heparin and the prevention of atherosclerosis. New York: Wiley-Liss Inc. 1990. 5. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990. 6. Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991.
620
Wyngaarden JB, Smith LH, eds. Cecil textbook of medicine. 18th ed. Philadelphia: WB Saunders, 1988. 8. West J, ed. Best and Taylor physiological basis of medical practice. 11th 7.
ed. Baltimore: Williams and Wilkins, 1985.
Guyton AC. Textbook of medical physiology. 7th ed. Philadelphia: WB Saunders, 1986. 10. Williams WJ, Beutler E, Ersler AJ, Lichtman MA, eds. Hematology. 4th 9.
ed. New York: McGraw-Hill, 1990.
Majerus PW, Broze CG Jr, Miletech JP, Tollefson DM. Anticoagulant, thrombolytic and antiplatelet drugs. Cited in Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990. 12. Sayen JJ, Singer RB, Pierce G, Horwitz O. Unstable angina, myocardial infarction, heparin and death: medium dose heparin (not exceeding 20 000 units/day) in the treatment of patients with acute coronary event—first year and long term comparative mortality. Trans Am Clin Climatol Assoc 1982; 94: 141-53. 13. Neri Serneri GG, Rovelli F, Gensini GF, Pirelli S, Camovali M, Fortini A. Effectiveness of low-dose heparin in prevention of myocardial reinfarction. Lancet 1987; 1: 937-42. 14. Samuels PH, Webster DR. The role of venous endothelium in the inception of thrombosis. Ann Surg 1952; 136: 422-38. 15. Zugibe FT. Mucopolysaccharides of the arterial wall. J Histochem Cytochem 1963; 11: 35-39. 16. Hiebert LM, Jaques LB. Heparin update on endothelium. Artery 1976; 11.
2: 26-37.
17. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976; 8: 195-204. 18. Heim CR, Des Prez R. Pulmonary embolism: a review. Adv Intern Med 1986; 31: 181-212. 19. Levine MN, Hirsh J. Hemorrhagic complications of anticoagulant therapy. Semin Thromb Hemost 1986; 12: 39-57. 20. Manufacturer’s product information package circular on heparin sodium USP injection. Kalamazoo: Upjohn. Revised May 1989. 21. Kakkar W. Low-dose heparin in the prevention of venous thromboembolism. In: Bradshaw RA, Wessler S, eds. Heparin: structure, function and clinical implications. New York: Plenum Press, 1974: 323-40. 22. Bick RL, Ross ES. Clinical use of intrapulmonary heparin. Semin Thromb Hemost 1985; 11: 213-17. 23. Hellgren M, Hagnevik K, Blomback M. Heparin aerosol—effect on blood coagulation and pulmonary function. Thromb Res 1981; 21: 493-502. 24. Kanabrocki EL, Sothem RB, Olwin JH, et al. Intrapulmonary administration of heparin in the morning and its effect upon blood variables. In: Reinberg A, Smolensky M, Labrecque G., eds. Annual reviews in chronopharmacology, vol 7. New York: Pergamon Press, 1990: 169-72. 25. Jaques LB, Wice SH, Hiebert LM. Evidence from endothelium of the gastric absorption of heparin and of dextran sulfates 8000. J Lab Clin Med 1991; 117: 122-30. 26. Consensus conference: prevention of venous thrombosis and pulmonary embolism. JAMA 1986; 256: 744-49.
BOOKSHELF Medical
Management of
Breast Cancer
Edited by Trevor J. Powles and Ian E. Smith. London: Martin Dunitz. 1991. Pp 345. 49.95/$110. ISBN 1-853170755.
Powles and Smith’s book opens with the potentially controversial statement that "Breast cancer is more of a medical than a surgical problem". But medical interventions probably do have most scope for further improvement in breast cancer prognosis and patients’ quality of life. The international array of authors assembled here shows a good balance between contributors from North America, the UK, and mainland Europe. Indeed, balance is the strength of this book: contentious areas are highlighted - and well discussed throughout, but the authors are also allowed to present their own views and assessment of published evidence on medical management of patients with breast cancer; where they might take up a controversial viewpoint the editors provide cross-references to conflicting opinions. There have been many recent advances in our knowledge of the biology of breast cancer, and growth factors, endocrinology, osteolysis, and systemic therapy are reviewed succinctly. There are up-to-date discussions of all the major endocrine therapies, with some of the new aromatase inhibitors and LHRH analogues included; chemotherapy is well covered, and the debates about dose intensification and high-dose chemotherapy for recurrent disease are analysed, as are novel agents. A vital consideration, often overlooked, is the patient’s quality of life during chemotherapy and the improvements that might occur with response to treatment, highlighted here in a chapter by Coates. Henderson and colleagues review recent advances in adjuvant therapy, and a good attempt is made to interpret these results in the light of our knowledge of the underlying biological processes: this helpful analysis should provide a sound basis for the design of future studies. Researchers with experience of primary medical treatment before surgery (neoadjuvant therapy) present their data, and chemoprevention of breast cancer in high-risk patients is well discussed.
Unfortunately, most patients with breast cancer will, if it recurs, eventually die from their disease, but much can be done to improve their quality of life and control their symptoms; there is an excellent section on palliative medicine, symptom control, and management of various common problems. Local recurrence after combined firstline treatment (eg, surgery and radiotherapy with or without chemotherapy or hormone treatment) is perhaps one topic that merits more discussion than it receives here; increased use of adjuvant therapies is likely to make the choice of treatment more
difficult.
Authors and editors have done their tasks well. Medical Management of Breast Cancer is very well laid out and includes references from 1990; each chapter is about 10 pages long-succinct, up to date, and clear. Any physician who looks after patients with breast cancer will enjoy this book, and it can be strongly recommended to trainee oncologists as a concise and readable review of many areas of clinical research interest. Nurses will also find much of value. The high quality of individual chapters and the large amount of information conveyed so painlessly makes the price seem very reasonable. ICRF Clinical Oncology Unit, University of Oxford, Oxford OX3 7LJ, UK
The
ADRIAN L. HARRIS
Psychoses of Epilepsy
Michael R. Trimble. New York: Raven. 1991. $77.50/45. ISBN 0-881677396.
Pp
210.
Trimble has a particular gift for books of this sort: he can be didactic but not pedantic, meticulous without being obsessional, and broad but not over-inclusive. As a result, The Psychoses of Epilepsy can be read with interest by students or postgraduates in any relevant discipline. He sets out a helpful historical background, justifies and explains the process of classification in epileptology and psychiatry, and provides an anatomical and physiological update from which base to launch his exposition on the psychoses.
