- Email: [email protected]
Sheffield risk and treatment table for primary prevention of coronary heart disease
THE LANCET
hypertension, which is done routinely and remains better than the cost of renal dialysis (about £28 000 per life year saved).5 With the vast morbidity and mortality costs, not to say social costs, associated with coronary heart disease in the UK, primary prevention of coronary heart disease seems to be a reasonable use of health resources. *A S Wierzbicki, T M Reynolds *Department of Chemical Pathology, St Thomas’ Hospital, London SE1 7EH, UK; and Burton Hospital, Burton-on-Trent
1
2
3
4
5
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Wierzbicki AS, Reynolds TM. Sheffield risk and treatment table for cholesterol lowering in prevention of coronary heart disease. Lancet 1996; 347: 466–67. Megnien JL, Levenson J, Simon A. Sheffield risk and treatment table for cholesterol lowering in prevention of coronary heart disease. Lancet 1996; 347: 468. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. New Engl J Med 1995; 333: 1301–07. Jonsson B. Measurement of health outcome and associated costs of cardiovascular disease. Eur Heart J 1996; 17 (suppl A): 2–7.
SIR—Ramsey and colleagues1 have set themselves a difficult task in attempting to codify the probable CHD event rates associated with specific serum cholesterol concentrations and other concomitant CHD risk factors. That they continue to achieve this will no doubt increase the awareness of the importance of such risk factors. We believe, however, that in laying emphasis on hypertension, smoking, left ventricular hypertrophy, and diabetes, while relegating bad family history to a footnote, they are reinforcing the lack of awareness about both the prevalence and importance of the monogenic dyslipidaemias such as familial hypercholesterolaemia and familial combined hyperlipidaemia. Although substantially underdiagnosed in the UK, such conditions are common (prevalence 1%,2 compared with 0·75% for type II diabetes3), and carry a high CHD event risk. We would reiterate the recommendations of the British Hyperlipidaemia Association,4 that the treatment of monogenic dyslipidaemia should be afforded the same priority as the treatment of other risk factors for CHD (such as those detailed in the Sheffield table). We believe that family history of CHD should figure prominently in future versions of these and other guidelines. *J C Chamberlain, W D Fraser Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L7 8X P, UK
1
SIR—The Sheffield risk table for targeting lipid lowering drug therapy1 is an advance on many previous recommendations. First, treatment decisions are based explicitly on an estimate of a patient’s outlook without treatment (肁3% per year) and the probable absolute benefit of treatment (聿20 patients need to be treated for 5 years to prevent one coronary heart disease [CHD] event). Second, the cost of treatment (聿£10 000 per year of life gained) is explicitly considered. However, the predictive validity of the Sheffield table could be much improved by substituting the total cholesterol value in the table with the total cholesterol to HDL-cholesterol ratio.2 Lipid modifying treatment is likely to be lifelong in most cases and it makes little sense to start this therapy without measuring HDL cholesterol. As an example, the Sheffield table indicates that a 52-year-old man who has hypertension and smokes will have a CHD risk of about 3% per year when his total cholesterol is 6·3 mmol/L. If his HDL cholesterol is 1·2 mmol/L, his total cholesterol would have to be 9·0 mmol/L to give a CHD risk of 3% per year (note; the Sheffield table estimation of CHD risk in this man assumes an HDL-cholesterol value of about 0·9 mmol/L). In addition, the decision by Ramsay and colleagues to use a cutoff of CHD risk of 3% per year clearly needs further debate. The translation of this cutoff level into a cost per year of life gained is a sensible first step. The next step is to compare the cost-effectiveness of lipid-lowering drug therapy with other potential uses of health care resources. The simplest comparison would be other approaches to CHD prevention—for example, smoking cessation, dietary interventions, or blood pressure lowering therapy. For some patients with dyslipidaemia, the most costeffective method of lowering CHD risk could be to lower their blood pressure with a low-dose diuretic. Rodney Jackson Centre for Evidence-Based Medicine, University of Oxford, Oxford OX1 3SE, UK
1
2
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Anderson KM, Wilson PWF, Odell PW, Kannel WB. An updated coronary risk profile: a statement for health professionals. Circulation 1991; 83: 356–62.
1040
2
3
4
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Standing Medical Advisory Committee. Blood cholesterol testing: the cost-effectiveness of opportunistic cholesterol testing. Report to the Secretary of State for Health. HM Stationery Office, London, 1990. Neill HAW, Thorogood M, Fowler GH, Hill RD, Mann JD. The Oxford Community Diabetes Study: evidence for an increase in the prevalence of known diabetes in Great Britain. Diabet Med 1987; 4: 539–43. Betteridge DJ, Dodson PM, Durrington PN, et al. Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association. Postgrad Med J 1993; 69: 359–69.
Authors’ reply SIR—We welcome debate on the level of coronary risk that might be targeted for primary prevention with statin treatment. Wierzbicki and Reynolds favour treatment at the risk level of participants in WOSCOPS.1 We agree that this is desirable, and justifiable on risk-benefit considerations, but fear that it is not feasible. It is indeed more costeffective than renal dialysis, but of course renal dialysis is not required by a quarter of adults. Statin treatment targeted at the WOSCOPS risk level would entail treatment of about 25% of all adults in the English population.2 At current prices this might cost £55 million per million of the population,2 totalling over £3 billion per year, or about 80% of the cost of all dispensed prescriptions in England in 1994–95. Comparison with antihypertensive treatment is far from straightforward,2 but treating hypertension is certainly much more costeffective than they imply. For example, treatment of middle-aged men with diastolic pressure 100–104 mm Hg costs about £100 per life year gained.3 We agree entirely with Jackson that treatment of hypertension should have priority where appropriate on grounds of costeffectiveness, and it is for this reason that the Sheffield table should be used after control of systolic blood pressure to 160 mm Hg, in accord with current British Hypertension Society guidelines.4 With respect to the technical aspects of the table, agevariable definitions of hypertension are irrelevant, whereas the age-related risk associated with blood pressure is important and an integral feature. Dichotomising systolic blood pressure does sacrifice accuracy for the sake of simplicity to some extent. However, it would be surprising if
Vol 348 • October 12, 1996
THE LANCET
the Joint European Task Force Guidelines are “far better” as regards accuracy. The Sheffield table, despite its much simpler format, includes two major risk factors missing from the European Task Force table—diabetes and left ventricular hypertrophy. HDL cholesterol is the only risk factor in the Framingham function to be omitted from the Sheffield table, and has been assigned population average values of 1·15 mmol/L for men, and 1·4 mmol/L for women. Jackson correctly suggests that the total cholesterol to HDLcholesterol ratio can be incorporated readily, and this does improve accuracy (in preparation). However, we are uncertain whether the resulting table would be as acceptable to ordinary doctors—an overriding concern for us. Chamberlain and Fraser highlight the issue of monogenic dyslipidaemias, and the absence of family history from the Sheffield table (and the Framingham risk function). In fact, family history is a fairly weak independent predictor of CHD risk when compared with the risk factors included,5 and remains so even when age of parental death or the death of one or both parents is included.5 Nevertheless, it is not our intention that those with a very strong family history should not be screened, or that those with familial dyslipidaemias should be denied drug treatment. For this reason family history is quite properly a footnote to the table. *L E Ramsay, I U Haq, P R Jackson, W W Yeo University Department of Medicine and Pharmacology, Section of Clinical Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1
2
3 4
5
Shepherd J, Cobbe SM, Ford I, et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR, Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Jönsson B. Measurement of health outcome and associated costs in cardiovascular disease. Eur Heart J 1996; 17(suppl A): 2–7. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993; 306: 983–87. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: strategy for use in general practice. BMJ 1986; 293: 474–79.
On May 30, lamotrigine 25 mg every other day was added. 12 days later she reacted with a flare, at first suspected to be caused by exposure to sun. On June 12 the flare had increased, and lamotrigine was stopped. 2 days later the reaction had progressed and her skin was starting to peel. A skin biopsy confirmed early TEN. She was transferred to the burns unit, where she was treated with plasmapheresis and put on positive-pressure ventilation. After a week, 40% of her skin was involved. She improved and was transferred to her local hospital on July 9. Genotyping did not reveal mutations in the genes of the drug-metabolising enzymes N-acetyltransferase 2, cytochromes P450 2D6 and 2C19, nor in the promoter of the UDP-glucuronosyltransferase 1*1 gene. A 22-year-old man given valproic acid 2400 mg daily and for the past 3 months lamotrigine 75 mg daily, is being treated in the burns unit for TEN involving all his skin. Rash develops in about 5% of patients starting lamotrigine.1 It appears to be related to the rate at which the drug is introduced, which is why gradual dose escalation has been recommended.1 The pathogenesis of TEN is still unknown, but may be an immunological hypersensitivity.2 All the patients in this report reacted within 14 days, which is compatible with the development of immune sensitisation.2 Another possible mechanism is altered drug metabolism resulting in reactions mediated by toxic intermediate metabolites.2 Lamotrigine is predominantly metabolised by glucuronidation, and it has been shown that patients with Gilbert’s syndrome, who have defective glucuronidation, have a lower clearance of lamotrigine,3 but the most common mutation causing this syndrome4 was not found in patient 2. However, all patients had co-medication with valproic acid, which interacts with the metabolism of lamotrigine by inhibiting its glucuronidation.5 The incidence of rash of lamotrigine is especially high when combined with valproic acid,1 but it is not known if the risk of developing TEN is higher. *Mia Wadelius, Torbjörn Karlsson, Claes Wadelius, Anders Rane Departments of *Clinical Pharmacology, Anaesthesiology, and Clinical Genetics, University Hospital, S-751 85 Uppsala, Sweden
1
Lamotrigine and toxic epidermal necrolysis SIR—Eight cases of severe skin reactions associated with lamotrigine have been reported in Sweden since 1994. Four of the reports concern Stevens-Johnson’s syndrome (SJS), and four of them toxic epidermal necrolysis (TEN). We describe here three lamotrigine-induced cases of TEN reported to the Regional Pharmacovigilance Centre in Uppsala. A 22-year-old woman with generalised epilepsy was treated with valproic acid 1500 mg daily. Because of inadequate seizure control, lamotrigine was added on April 14, when valproic acid was decreased to 1300 mg daily. On the twelfth day of medication she sunbathed in a solarium. She reacted with an intense flare, which rapidly progressed to blisters and fever, at first suspected to be a phototoxic reaction. Lamotrigine was discontinued, but the reaction progressed. She was transferred to the burns unit on May 2. TEN was verified by skin biopsy, and treatment with plasmapheresis was started. On May 5, when the toxic epidermal necrolysis involved her trachea and 70% of her skin, she was put on mechanical ventilation because of pain. After 3 weeks in the burns unit she was transferred to her local hospital. A 21-year-old mentally retarded woman with intractable temporal lobe epilepsy was treated with valproic acid 720 mg daily, levothyroxine, and medroxyprogesterone.
Vol 348 • October 12, 1996
2
3
4
5
Brodie MJ. Lamotrigine versus other antiepileptic drugs: a star rating system is born. Epilepsia 1994; 35 (suppl 5): S41–S46. Friedmann PS, Strickland I, Pirmohamed M, Park BK. Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994; 130: 598–604. Park BK, Kitteringham NR, Pirmohamed M, Tucker GT. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41: 477–91. Bosma P, Chowdhury RJ, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13.
Regression of MALT lymphoma and treatment for Helicobacter pylori SIR—Alkan and colleagues (July 27, p 268)1 report the disappearance of a salivary gland MALT lymphoma coincident with treatment for helicobacter-associated gastritis. Their conclusions are unacceptable on the evidence presented. A large proportion of 62-year-old Asians in the USA would be expected to harbour Helicobacter pylori in the stomach. Thus the association of the salivary tumour with H pylori-associated gastritis could be purely coincidental—it cannot be cited as evidence that helicobacter produced the lymphoma. Additionally, treatment was given to eliminate helicobacter, but no evidence is presented to show that this
1041
hypertension, which is done routinely and remains better than the cost of renal dialysis (about £28 000 per life year saved).5 With the vast morbidity and mortality costs, not to say social costs, associated with coronary heart disease in the UK, primary prevention of coronary heart disease seems to be a reasonable use of health resources. *A S Wierzbicki, T M Reynolds *Department of Chemical Pathology, St Thomas’ Hospital, London SE1 7EH, UK; and Burton Hospital, Burton-on-Trent
1
2
3
4
5
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Wierzbicki AS, Reynolds TM. Sheffield risk and treatment table for cholesterol lowering in prevention of coronary heart disease. Lancet 1996; 347: 466–67. Megnien JL, Levenson J, Simon A. Sheffield risk and treatment table for cholesterol lowering in prevention of coronary heart disease. Lancet 1996; 347: 468. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. New Engl J Med 1995; 333: 1301–07. Jonsson B. Measurement of health outcome and associated costs of cardiovascular disease. Eur Heart J 1996; 17 (suppl A): 2–7.
SIR—Ramsey and colleagues1 have set themselves a difficult task in attempting to codify the probable CHD event rates associated with specific serum cholesterol concentrations and other concomitant CHD risk factors. That they continue to achieve this will no doubt increase the awareness of the importance of such risk factors. We believe, however, that in laying emphasis on hypertension, smoking, left ventricular hypertrophy, and diabetes, while relegating bad family history to a footnote, they are reinforcing the lack of awareness about both the prevalence and importance of the monogenic dyslipidaemias such as familial hypercholesterolaemia and familial combined hyperlipidaemia. Although substantially underdiagnosed in the UK, such conditions are common (prevalence 1%,2 compared with 0·75% for type II diabetes3), and carry a high CHD event risk. We would reiterate the recommendations of the British Hyperlipidaemia Association,4 that the treatment of monogenic dyslipidaemia should be afforded the same priority as the treatment of other risk factors for CHD (such as those detailed in the Sheffield table). We believe that family history of CHD should figure prominently in future versions of these and other guidelines. *J C Chamberlain, W D Fraser Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool L7 8X P, UK
1
SIR—The Sheffield risk table for targeting lipid lowering drug therapy1 is an advance on many previous recommendations. First, treatment decisions are based explicitly on an estimate of a patient’s outlook without treatment (肁3% per year) and the probable absolute benefit of treatment (聿20 patients need to be treated for 5 years to prevent one coronary heart disease [CHD] event). Second, the cost of treatment (聿£10 000 per year of life gained) is explicitly considered. However, the predictive validity of the Sheffield table could be much improved by substituting the total cholesterol value in the table with the total cholesterol to HDL-cholesterol ratio.2 Lipid modifying treatment is likely to be lifelong in most cases and it makes little sense to start this therapy without measuring HDL cholesterol. As an example, the Sheffield table indicates that a 52-year-old man who has hypertension and smokes will have a CHD risk of about 3% per year when his total cholesterol is 6·3 mmol/L. If his HDL cholesterol is 1·2 mmol/L, his total cholesterol would have to be 9·0 mmol/L to give a CHD risk of 3% per year (note; the Sheffield table estimation of CHD risk in this man assumes an HDL-cholesterol value of about 0·9 mmol/L). In addition, the decision by Ramsay and colleagues to use a cutoff of CHD risk of 3% per year clearly needs further debate. The translation of this cutoff level into a cost per year of life gained is a sensible first step. The next step is to compare the cost-effectiveness of lipid-lowering drug therapy with other potential uses of health care resources. The simplest comparison would be other approaches to CHD prevention—for example, smoking cessation, dietary interventions, or blood pressure lowering therapy. For some patients with dyslipidaemia, the most costeffective method of lowering CHD risk could be to lower their blood pressure with a low-dose diuretic. Rodney Jackson Centre for Evidence-Based Medicine, University of Oxford, Oxford OX1 3SE, UK
1
2
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Anderson KM, Wilson PWF, Odell PW, Kannel WB. An updated coronary risk profile: a statement for health professionals. Circulation 1991; 83: 356–62.
1040
2
3
4
Ramsay LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88. Standing Medical Advisory Committee. Blood cholesterol testing: the cost-effectiveness of opportunistic cholesterol testing. Report to the Secretary of State for Health. HM Stationery Office, London, 1990. Neill HAW, Thorogood M, Fowler GH, Hill RD, Mann JD. The Oxford Community Diabetes Study: evidence for an increase in the prevalence of known diabetes in Great Britain. Diabet Med 1987; 4: 539–43. Betteridge DJ, Dodson PM, Durrington PN, et al. Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association. Postgrad Med J 1993; 69: 359–69.
Authors’ reply SIR—We welcome debate on the level of coronary risk that might be targeted for primary prevention with statin treatment. Wierzbicki and Reynolds favour treatment at the risk level of participants in WOSCOPS.1 We agree that this is desirable, and justifiable on risk-benefit considerations, but fear that it is not feasible. It is indeed more costeffective than renal dialysis, but of course renal dialysis is not required by a quarter of adults. Statin treatment targeted at the WOSCOPS risk level would entail treatment of about 25% of all adults in the English population.2 At current prices this might cost £55 million per million of the population,2 totalling over £3 billion per year, or about 80% of the cost of all dispensed prescriptions in England in 1994–95. Comparison with antihypertensive treatment is far from straightforward,2 but treating hypertension is certainly much more costeffective than they imply. For example, treatment of middle-aged men with diastolic pressure 100–104 mm Hg costs about £100 per life year gained.3 We agree entirely with Jackson that treatment of hypertension should have priority where appropriate on grounds of costeffectiveness, and it is for this reason that the Sheffield table should be used after control of systolic blood pressure to 160 mm Hg, in accord with current British Hypertension Society guidelines.4 With respect to the technical aspects of the table, agevariable definitions of hypertension are irrelevant, whereas the age-related risk associated with blood pressure is important and an integral feature. Dichotomising systolic blood pressure does sacrifice accuracy for the sake of simplicity to some extent. However, it would be surprising if
Vol 348 • October 12, 1996
THE LANCET
the Joint European Task Force Guidelines are “far better” as regards accuracy. The Sheffield table, despite its much simpler format, includes two major risk factors missing from the European Task Force table—diabetes and left ventricular hypertrophy. HDL cholesterol is the only risk factor in the Framingham function to be omitted from the Sheffield table, and has been assigned population average values of 1·15 mmol/L for men, and 1·4 mmol/L for women. Jackson correctly suggests that the total cholesterol to HDLcholesterol ratio can be incorporated readily, and this does improve accuracy (in preparation). However, we are uncertain whether the resulting table would be as acceptable to ordinary doctors—an overriding concern for us. Chamberlain and Fraser highlight the issue of monogenic dyslipidaemias, and the absence of family history from the Sheffield table (and the Framingham risk function). In fact, family history is a fairly weak independent predictor of CHD risk when compared with the risk factors included,5 and remains so even when age of parental death or the death of one or both parents is included.5 Nevertheless, it is not our intention that those with a very strong family history should not be screened, or that those with familial dyslipidaemias should be denied drug treatment. For this reason family history is quite properly a footnote to the table. *L E Ramsay, I U Haq, P R Jackson, W W Yeo University Department of Medicine and Pharmacology, Section of Clinical Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1
2
3 4
5
Shepherd J, Cobbe SM, Ford I, et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR, Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Jönsson B. Measurement of health outcome and associated costs in cardiovascular disease. Eur Heart J 1996; 17(suppl A): 2–7. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993; 306: 983–87. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: strategy for use in general practice. BMJ 1986; 293: 474–79.
On May 30, lamotrigine 25 mg every other day was added. 12 days later she reacted with a flare, at first suspected to be caused by exposure to sun. On June 12 the flare had increased, and lamotrigine was stopped. 2 days later the reaction had progressed and her skin was starting to peel. A skin biopsy confirmed early TEN. She was transferred to the burns unit, where she was treated with plasmapheresis and put on positive-pressure ventilation. After a week, 40% of her skin was involved. She improved and was transferred to her local hospital on July 9. Genotyping did not reveal mutations in the genes of the drug-metabolising enzymes N-acetyltransferase 2, cytochromes P450 2D6 and 2C19, nor in the promoter of the UDP-glucuronosyltransferase 1*1 gene. A 22-year-old man given valproic acid 2400 mg daily and for the past 3 months lamotrigine 75 mg daily, is being treated in the burns unit for TEN involving all his skin. Rash develops in about 5% of patients starting lamotrigine.1 It appears to be related to the rate at which the drug is introduced, which is why gradual dose escalation has been recommended.1 The pathogenesis of TEN is still unknown, but may be an immunological hypersensitivity.2 All the patients in this report reacted within 14 days, which is compatible with the development of immune sensitisation.2 Another possible mechanism is altered drug metabolism resulting in reactions mediated by toxic intermediate metabolites.2 Lamotrigine is predominantly metabolised by glucuronidation, and it has been shown that patients with Gilbert’s syndrome, who have defective glucuronidation, have a lower clearance of lamotrigine,3 but the most common mutation causing this syndrome4 was not found in patient 2. However, all patients had co-medication with valproic acid, which interacts with the metabolism of lamotrigine by inhibiting its glucuronidation.5 The incidence of rash of lamotrigine is especially high when combined with valproic acid,1 but it is not known if the risk of developing TEN is higher. *Mia Wadelius, Torbjörn Karlsson, Claes Wadelius, Anders Rane Departments of *Clinical Pharmacology, Anaesthesiology, and Clinical Genetics, University Hospital, S-751 85 Uppsala, Sweden
1
Lamotrigine and toxic epidermal necrolysis SIR—Eight cases of severe skin reactions associated with lamotrigine have been reported in Sweden since 1994. Four of the reports concern Stevens-Johnson’s syndrome (SJS), and four of them toxic epidermal necrolysis (TEN). We describe here three lamotrigine-induced cases of TEN reported to the Regional Pharmacovigilance Centre in Uppsala. A 22-year-old woman with generalised epilepsy was treated with valproic acid 1500 mg daily. Because of inadequate seizure control, lamotrigine was added on April 14, when valproic acid was decreased to 1300 mg daily. On the twelfth day of medication she sunbathed in a solarium. She reacted with an intense flare, which rapidly progressed to blisters and fever, at first suspected to be a phototoxic reaction. Lamotrigine was discontinued, but the reaction progressed. She was transferred to the burns unit on May 2. TEN was verified by skin biopsy, and treatment with plasmapheresis was started. On May 5, when the toxic epidermal necrolysis involved her trachea and 70% of her skin, she was put on mechanical ventilation because of pain. After 3 weeks in the burns unit she was transferred to her local hospital. A 21-year-old mentally retarded woman with intractable temporal lobe epilepsy was treated with valproic acid 720 mg daily, levothyroxine, and medroxyprogesterone.
Vol 348 • October 12, 1996
2
3
4
5
Brodie MJ. Lamotrigine versus other antiepileptic drugs: a star rating system is born. Epilepsia 1994; 35 (suppl 5): S41–S46. Friedmann PS, Strickland I, Pirmohamed M, Park BK. Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994; 130: 598–604. Park BK, Kitteringham NR, Pirmohamed M, Tucker GT. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41: 477–91. Bosma P, Chowdhury RJ, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13.
Regression of MALT lymphoma and treatment for Helicobacter pylori SIR—Alkan and colleagues (July 27, p 268)1 report the disappearance of a salivary gland MALT lymphoma coincident with treatment for helicobacter-associated gastritis. Their conclusions are unacceptable on the evidence presented. A large proportion of 62-year-old Asians in the USA would be expected to harbour Helicobacter pylori in the stomach. Thus the association of the salivary tumour with H pylori-associated gastritis could be purely coincidental—it cannot be cited as evidence that helicobacter produced the lymphoma. Additionally, treatment was given to eliminate helicobacter, but no evidence is presented to show that this
1041