488
LETTERS to the EDITOR
Wrong lesson from Finnish trial of cardiovascular disease prevention SIR,-Publicity about a report on the latest fmdings of a trial of multifactorial primary prevention of cardiovascular disease1 reveals an interesting bias in medical opinion. For instance, the Sunday Times of Dec 22, 1991, carried a front-page article headed "Cutting cholesterol can increase risk of heart disease". The "healthy disquiet" encouraged by the report itself2 was generally taken to mean that the benefits of cholesterol-lowering must yet again be put on public trial. In our view, the disquiet engendered by this trial is very different. 1200 men were randomly assigned to an intervention group receiving intensive drug treatment to reduce moderately raised serum cholesterol and blood pressure or to a control group who received usual medical care from their own doctors. The trial lasted 5 years during which time 37% of the intervention group received lipid-lowering medication (clofibrate and/or probucol) and 32% received antihypertensive drugs (mainly propranolol, pindolol, hydrochlorothiazide, amiloride). ProbucoP and propranolo14lower serum high-density lipoprotein (HDL) cholesterol and thiazide diuretics raise total serum cholesterol.5 Clofibrate, by marginally raising HDL and lowering low-density lipoproteins, would tend to reverse these effects.6 At the end of the trial the ratio of cholesterol to HDL cholesterol was identical (6-0) in the intervention group and the controls, so in no sense was this a trial of lipid modification, since all that clofibrate achieved was a restoration of the average lipid profile to control values. At the end of the trial cardiac death rates were similar in the control and intervention groups, but there was excess coronary heart disease morbidity associated with betaadrenoreceptor blockade, but not with lipid-lowering therapy.? After the trial, lipid-lowering medication was stopped in all but 2% of the intervention group whereas 27% continued on antihypertensive treatment. At the end of the trial, only 15% of the controls were receiving antihypertensive therapy and even 10 years afterwards only 22% were. The intervention group therefore received some 2700 man-years exposure to antihypertensive medication as opposed to 1500 man-years in the control group. During the 10 years in which antihypertensive drugs but not lipid-lowering medication were used, a highly significant and progressively greater rate of cardiac death occurred in the intervention group. So why the renewed clamour against lipid-lowering drugs? Perhaps for them it is a case of "give a dog a bad name" whereas antihypertensive treatment is forever the "blue-eyed boy".8 Department of Medicine, University of Manchester, Royal Infirmary, Manchester M13 9WL, UK
P. N. DURRINGTON D. BHATNAGAR
Strandberg TE, Salomaa VV, Maukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long-term mortality after 5 years multifactorial primary prevention of cardiovascular disease in middle-aged men. JAMA 1991; 266: 1225-29. 2. Oglesby P, Hennekens CH. The latest report from Finland: a lesson in expectations. JAMA 1991; 266: 1267-68. 3. Durrington PN, Miller JP. Double-blind, placebo-controlled, cross-over trial of probucol in heterozygous familial hypercholesterolaemia. Atherosclerosis 1985; 55: 1.
187-94. 4. Miller NE. Effects of adrenoceptor-blocking drugs on plasma lipoprotein concentrations. Am J Cardiol 1987; 60: 17E-23E. 5. Ames RP. The effects of antihypertensive drugs on serum lipids and lipoproteins I. Diuretics Drugs 1986; 32: 260-78. 6. Durrington PN. Hyperlipidaemia: diagnosis and treatment. London. Wright, 1989. 7. Miettinen TA, Huttunen JK, Naukkarinen V, et al. Multifactorial primary prevention of cardiovascular diseases in middle-aged men JAMA 1985; 254: 2097-102. 8. Steinberg D The cholesterol controversy is over: why did it take so long? Circulation 1989; 80: 1070-78.
Eosinophilia associated with clozapine p 1520) describe a of eosinophilia during challenge with clozapine, and point out that medical practitioners prescribing clozapine may not be aware of the risk of eosinophilia. In Finland, clozapine-associated eosinophilia has been a well-known adverse effect since the 1980s; since Finnish patients seem to have a greater risk for haematological adverse effects,! patients receiving clozapine have been monitored carefully. We have been involved in several cases of leucocytosis and eosinophilia with clozapine treatment during the past five years. The latest case of eosinophilia was detected in November, 1991. A 38-year-old female schizophrenic patient was transferred from a local mental hospital to a state mental hospital because of severe aggressive behaviour in July, 1991. Clozapine treatment was started in after September zuclopenthixol, chlorprothixene, chlorpromazine, and carbamazepine proved ineffective. Leucocyte values and differential count were normal before treatment was started. After five weeks leucocyte count had increased to 11x109/1, of which 0-7 x 1Q9/1 were eosinophils. A week later leucocyte count was 13-9 x 10/1, and eosinophils were 14 x 109/1. Another week later the eosinophil count had increased to 1.5 x 109/1, and clozapine was discontinued. However, four days later leucocyte number and differential count had returned to normal, and clozapine has been continued ever since. In the weekly controls, a single transitory abnormal leucocyte value of 20-7 x 109/1 (with a normal differential count) was seen at the end of December. She had no somatic disease that could have explained leucocytosis and
SIR,-Dr Stricker and Dr Tielens (Dec 14,
case
eosinophilia. In Finland, Sandoz provides these instructions about eosinophilia during clozapine treatment: if the absolute number of eosinophils is over l’4xx 109/1, clozapine should be discontinued immediately. When the absolute number of eosinophils is raised but is below l’4x10**/!, leucocyte and eosinophil counts should be checked every week, and clozapine treatment can be continued if eosinophils are not increasing. A haematologist should be consulted if the number of leucocytes remains over 15 x 109/1 without any other obvious reason. There seem to be no generally acknowledged procedures for the management of clozapine-associated eosinophilia outside Finland. We think that these procedures might be useful in other countries. Niuvanniemi Hospital, SF-70240 Kuopio, Finland
J. TIIHONEN J. PAANILA
Chapelle A, Kari C, Nurminen M, Hemberg S. Clozapine-induced agranulocytosis: a genetic and epidemiological study. Hum Genet 1977; 37: 184-94.
1. De la
psychotic disorder in hepatic encephalopathy
Flumazenil-induced
SIR,-Hepatic encephalopathy (HE) contributes substantially to morbidity and mortality in cirrhosis. Successful treatment of HE with flumazenil, a selective benzodiazepine antagonist, has been reported,1,2 the rationale being the blocking ofy-aminobutyric acid (GABA) receptors, which also bind benzodiazepines. The administration of flumazenil to patients with HE has been shown to improve neurological symptoms, probably by inhibiting the binding of endogenous ligands,3without specific side-effects.’ Ferenci et al2 described a patient on successful long-tenm prophylaxis of relapsing HE with oral flumazenil who experienced slight and transient anxiety after each dose. Here we report a severe acute psychotic disorder associated with flumazenil in a patient with HE.
LETTERS to the EDITOR
Wrong lesson from Finnish trial of cardiovascular disease prevention SIR,-Publicity about a report on the latest fmdings of a trial of multifactorial primary prevention of cardiovascular disease1 reveals an interesting bias in medical opinion. For instance, the Sunday Times of Dec 22, 1991, carried a front-page article headed "Cutting cholesterol can increase risk of heart disease". The "healthy disquiet" encouraged by the report itself2 was generally taken to mean that the benefits of cholesterol-lowering must yet again be put on public trial. In our view, the disquiet engendered by this trial is very different. 1200 men were randomly assigned to an intervention group receiving intensive drug treatment to reduce moderately raised serum cholesterol and blood pressure or to a control group who received usual medical care from their own doctors. The trial lasted 5 years during which time 37% of the intervention group received lipid-lowering medication (clofibrate and/or probucol) and 32% received antihypertensive drugs (mainly propranolol, pindolol, hydrochlorothiazide, amiloride). ProbucoP and propranolo14lower serum high-density lipoprotein (HDL) cholesterol and thiazide diuretics raise total serum cholesterol.5 Clofibrate, by marginally raising HDL and lowering low-density lipoproteins, would tend to reverse these effects.6 At the end of the trial the ratio of cholesterol to HDL cholesterol was identical (6-0) in the intervention group and the controls, so in no sense was this a trial of lipid modification, since all that clofibrate achieved was a restoration of the average lipid profile to control values. At the end of the trial cardiac death rates were similar in the control and intervention groups, but there was excess coronary heart disease morbidity associated with betaadrenoreceptor blockade, but not with lipid-lowering therapy.? After the trial, lipid-lowering medication was stopped in all but 2% of the intervention group whereas 27% continued on antihypertensive treatment. At the end of the trial, only 15% of the controls were receiving antihypertensive therapy and even 10 years afterwards only 22% were. The intervention group therefore received some 2700 man-years exposure to antihypertensive medication as opposed to 1500 man-years in the control group. During the 10 years in which antihypertensive drugs but not lipid-lowering medication were used, a highly significant and progressively greater rate of cardiac death occurred in the intervention group. So why the renewed clamour against lipid-lowering drugs? Perhaps for them it is a case of "give a dog a bad name" whereas antihypertensive treatment is forever the "blue-eyed boy".8 Department of Medicine, University of Manchester, Royal Infirmary, Manchester M13 9WL, UK
P. N. DURRINGTON D. BHATNAGAR
Strandberg TE, Salomaa VV, Maukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long-term mortality after 5 years multifactorial primary prevention of cardiovascular disease in middle-aged men. JAMA 1991; 266: 1225-29. 2. Oglesby P, Hennekens CH. The latest report from Finland: a lesson in expectations. JAMA 1991; 266: 1267-68. 3. Durrington PN, Miller JP. Double-blind, placebo-controlled, cross-over trial of probucol in heterozygous familial hypercholesterolaemia. Atherosclerosis 1985; 55: 1.
187-94. 4. Miller NE. Effects of adrenoceptor-blocking drugs on plasma lipoprotein concentrations. Am J Cardiol 1987; 60: 17E-23E. 5. Ames RP. The effects of antihypertensive drugs on serum lipids and lipoproteins I. Diuretics Drugs 1986; 32: 260-78. 6. Durrington PN. Hyperlipidaemia: diagnosis and treatment. London. Wright, 1989. 7. Miettinen TA, Huttunen JK, Naukkarinen V, et al. Multifactorial primary prevention of cardiovascular diseases in middle-aged men JAMA 1985; 254: 2097-102. 8. Steinberg D The cholesterol controversy is over: why did it take so long? Circulation 1989; 80: 1070-78.
Eosinophilia associated with clozapine p 1520) describe a of eosinophilia during challenge with clozapine, and point out that medical practitioners prescribing clozapine may not be aware of the risk of eosinophilia. In Finland, clozapine-associated eosinophilia has been a well-known adverse effect since the 1980s; since Finnish patients seem to have a greater risk for haematological adverse effects,! patients receiving clozapine have been monitored carefully. We have been involved in several cases of leucocytosis and eosinophilia with clozapine treatment during the past five years. The latest case of eosinophilia was detected in November, 1991. A 38-year-old female schizophrenic patient was transferred from a local mental hospital to a state mental hospital because of severe aggressive behaviour in July, 1991. Clozapine treatment was started in after September zuclopenthixol, chlorprothixene, chlorpromazine, and carbamazepine proved ineffective. Leucocyte values and differential count were normal before treatment was started. After five weeks leucocyte count had increased to 11x109/1, of which 0-7 x 1Q9/1 were eosinophils. A week later leucocyte count was 13-9 x 10/1, and eosinophils were 14 x 109/1. Another week later the eosinophil count had increased to 1.5 x 109/1, and clozapine was discontinued. However, four days later leucocyte number and differential count had returned to normal, and clozapine has been continued ever since. In the weekly controls, a single transitory abnormal leucocyte value of 20-7 x 109/1 (with a normal differential count) was seen at the end of December. She had no somatic disease that could have explained leucocytosis and
SIR,-Dr Stricker and Dr Tielens (Dec 14,
case
eosinophilia. In Finland, Sandoz provides these instructions about eosinophilia during clozapine treatment: if the absolute number of eosinophils is over l’4xx 109/1, clozapine should be discontinued immediately. When the absolute number of eosinophils is raised but is below l’4x10**/!, leucocyte and eosinophil counts should be checked every week, and clozapine treatment can be continued if eosinophils are not increasing. A haematologist should be consulted if the number of leucocytes remains over 15 x 109/1 without any other obvious reason. There seem to be no generally acknowledged procedures for the management of clozapine-associated eosinophilia outside Finland. We think that these procedures might be useful in other countries. Niuvanniemi Hospital, SF-70240 Kuopio, Finland
J. TIIHONEN J. PAANILA
Chapelle A, Kari C, Nurminen M, Hemberg S. Clozapine-induced agranulocytosis: a genetic and epidemiological study. Hum Genet 1977; 37: 184-94.
1. De la
psychotic disorder in hepatic encephalopathy
Flumazenil-induced
SIR,-Hepatic encephalopathy (HE) contributes substantially to morbidity and mortality in cirrhosis. Successful treatment of HE with flumazenil, a selective benzodiazepine antagonist, has been reported,1,2 the rationale being the blocking ofy-aminobutyric acid (GABA) receptors, which also bind benzodiazepines. The administration of flumazenil to patients with HE has been shown to improve neurological symptoms, probably by inhibiting the binding of endogenous ligands,3without specific side-effects.’ Ferenci et al2 described a patient on successful long-tenm prophylaxis of relapsing HE with oral flumazenil who experienced slight and transient anxiety after each dose. Here we report a severe acute psychotic disorder associated with flumazenil in a patient with HE.
