- Email: [email protected]
Polycystic ovaries
and antivenom importance.
are
of
greater
*Fekri Abroug, Souheil ElAtrous, Semir Nouira, Habib Haguiga, Slah Bouchoucha *Intensive Care Unit, CHU F Bourguiba, Monastir Emergency Department, 5000 Monastir, Tunisia; and Hôpital Régional Tozeur, Tunisia (e-mail: [email protected]) 1
Abroug F, Nouira S, Haguiga H, et al. A randomised clinical trial of high-dose hydrocortisone hemisuccinate in scorpion envenomation. Ann Emerg Med 1997; 30: 245–58. 2 Ismail M, Fatani AJY, Dabees TT. Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallicrein-kinin inhibitors. Toxicon 1992; 30: 1257–79. 3 Tarasiuk A, Khvatskin S, Sofer S. Effects of antivenom serotherapy on hemodynamic pathophysiology in dogs injected with L quiquistriatus scorpion venom. Toxicon 1998; 36: 963–71. 4 Krifi MN, Elayeb M, Dellagi K. New procedures and parameters for better evaluation of Androctonus australis garzonii (Aag) and Buthus occitanus tunetanus (Bot) scorpion envenomation and specific serotherapy treatment. Toxicon 1996; 34: 257–66. 5 Abraham E. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med 1999; 25: 556–66.
Cushing’s disease Sir—Shinichi Kawai and colleagues (Sept 11, p 951) 1 correctly indicate the efficacy and tolerability of long-term low-dose mitotane in the control of cortisol production in patients with Cushing’s disease who are waiting for pituitary radiotherapy to reduce corticotropin drive. However, they do not mention that mitotane uniformly increases circulating cholesterol concentrations. We studied 21 patients with corticotropin-dependent Cushing’s syndrome treated for up to 77 months and assessed the mechanism of the hypercholesterolaemia. In all patients total serum cholesterol rose on initiation of mitotane therapy by a mean 68% (range 24–196), mainly by increasing LDL cholesterol. The mechanism of increase seemed to be mitotane inhibition of cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for downregulating cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reversed the hyperlipidaemia.2,3 Serum cholesterol is raised in untreated Cushing’s syndrome4 and cardiovascular events are the main cause of the excess mortality associated with this serious condition. 5 Long-term
68
mitotane therapy may control circulating cortisol concentrations, but is unlikely to reduce the risk of cardiovascular events if hypercholesterolaemia is induced and left untreated.
disease because of its sufficient efficacy and lower risk. Shinichi Kawai Institute of Medical Science, St Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan (e-mail: [email protected])
*Peter J Trainer, Michael Besser *Department of Endocrinology, Christie Hospital, Manchester M20 4BX, UK; and Department of Endocrinology, St Bartholomew’s Hospital, London (e-mail: [email protected]) 1
Kawai S, Ichikawa Y, Kaburaki J, Yoshida T. 18 years mitotane therapy for intractable Cushing’s disease. Lancet 1999; 354: 951. 2 Trainer PJ, Howlett TA, Besser GM. The medical management of Cushing’s syndrome using drugs acting on the adrenal cortex. In: Casanueva FF, Dieguez C, eds. Recent advances in basic and clinical neuroendocrinology. Amsterdam: Elsevier Science, 1989: 341–49. 3 Maher VMG, Trainer PJ, Scoppola A, Anderson JV, Thompson GR, Besser GM. Possible mechanism and treatment of o,p⬘DDD-induced hypercholesterolaemia. QJM 1992; 84: 671–79. 4 Taskinen M-R, Nikkila EA, Pelkonen R, Sane T. Plasma lipoproteins, lipolytic enzymes, and very low density lipoprotein triglyceride turnover in Cushing’s syndrome. J Clin Endocrinol Metab 1983; 57: 619–26. 5 Welbourn RB, Montgomery DA, Kennedy TL. The natural history of treated Cushing’s syndrome. Br J Surg 1971; 58: 1–16.
Author’s reply Sir—The serum total cholesterol concentration is increased by mitotane, as Peter Trainer and Michael Besser, and Luton and colleagues1 mention. Concentration initially increased to 8·71 mmol/L in our patient, but gradually decreased even though mitotane therapy was continued. The prognosis of untreated Cushing’s syndrome is poor, with the main causes of death being overwhelming infection and the consequences of hypertension or arteriosclerosis.2 Serious arteriosclerotic complications, such as cardiovascular events, may be explained by several coronary risk factors, including increased serum total or LDL cholesterol, hypertension, obesity, and glucose intolerance caused by hypercortisolaemia. When mitotane therapy is successful, risk of infection and coronary risk factors, except for transient hypercholesterolaemia, may decline. Even if a high serum cholesterol concentration persists, simvastatin or other statins may reverse it, as Trainer and Besser mention. This drug may suppress not only adrenal cortisol production, but also pituitary corticotropin secretion. Thus, longterm mitotane therapy is probably a good choice for intractable Cushing’s
1
Luton JP, Mahoudeau JA, Bouchard P, et al. Treatment of Cushing’s disease by O,p⬘DDD: survey of 62 cases. N Engl J Med 1979; 300: 459–64. 2 Christy NP, ed. Cushing’s syndrome: the natural disease. In: The human adrenal cortex. New York: Harper and Row, 1971: 359–94.
Polycystic ovaries Sir—In Adam Balen’s Sept 18 commentary,1 the reader is left with the impression that hyperinsulinaemia in polycystic ovary syndrome (PCOS) is a consequence of abnormal insulin gene expression rather than a compensatory response to peripheral insulin resistance. As Balen points out, the molecular events underlying PCOS remain unclear. However, hyperinsulinaemia, which exacerbates overproduction of ovarian androgens, is widely believed to occur as a result of peripheral insulin resistance. Studies to assess insulin resistance in women with PCOS by use of the hyperinsulinaemic euglycaemic clamp technique show a 30–40% decrease in insulin-mediated glucose disposal, similar in size to that seen in type 2 diabetes mellitus. 2 Insulin resistance is also seen ex vivo: adipocytes from women with PCOS show decreased insulin sensitivity and responsiveness to glucose uptake. 2 Resistance to insulin manifests itself as an increase in the prevalence of type 2 diabetes: 15% in postmenopausal women with PCOS versus 2·3% in controls matched by age and bodymass index.3 Importantly, insulin-receptormediated effects on ovarian steroidogenesis seem to be preserved in PCOS despite profound resistance to insulinmediated glucose uptake in other tissues, in that there is a selective defect of metabolic as opposed to mitogenic signalling pathways.4 Thus, the beneficial effects of drugs such as metformin and troglitazone2 (which have direct and indirect effects on peripheral carbohydrate metabolism) can be explained by reductions in compensatory insulin secretion by the pancreatic -cell. Such effects indicate that insulin resistance plays a primary pathophysiological role in PCOS, rather than being secondary to androgen excess. Because peripheral insulin resistance in PCOS may be associated with
THE LANCET • Vol 355 • January 1, 2000
premature cardiovascular disease (as in other disease states), resistance to insulin action in vascular tissue, which may be associated with endothelial dysfunction, is an important area of investigation. *Chris Kelly, John Petrie, Helen Lyall, Gwyn Gould, John Connell *Department of Medicine and Therapeutics, University of Glasgow, Glasgow G11 6NT, UK: Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary, Glasgow; and Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Science, University of Glasgow, Glasgow 1
Balen A. Pathogenesis of polycystic ovary syndrome—the enigma unravels? Lancet 1999; 354: 966–67. 2 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implication for pathogenesis. Endocr Rev 1997; 18: 774–800. 3 Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992; 57: 505–13. 4 Book C-B, Danaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999; 84: 3110–16.
Prevention of atherosclerosis in children Sir—Claudio Napoli and colleagues’ (Oct 9, p 1234)1 observation that children from hypercholesterolaemic mothers had more fatty streaks than children from normocholesterolaemic mothers is interesting, but their interpretation of the finding does not agree with present knowledge, or common sense. If the fatty streaks were early atherosclerotic lesions, why were they more common in the fetuses than in the children? Fatty streaks are found worldwide in almost all children, equally often in countries where atherosclerosis is rare, as in countries where it is frequent.2 The development of raised lesions later in life in some individuals must therefore be due to factors other than the mere presence of fatty streaks. Even if we assume that fatty streaks are the forerunners of raised lesions, there is no evidence for blaming a high maternal cholesterol concentration or atherogenic genes; the difference in streak frequency may be due to any hereditary or environmental factor associated with high cholesterol concentrations. To use Napoli and colleagues’ findings as an argument for cholesterol concentration lowering in childhood, as did Berenson and Srinivasan in their commentary,3 seems unfounded. As Napoli and colleagues emphasise, cholesterol concentration was normal
THE LANCET • Vol 355 • January 1, 2000
and similar in both groups, and the fatty streaks cannot therefore have been caused by high concentrations in the child. Even if the fatty streaks had been caused by high concentrations, the predictive value of cholesterol screening is low because concentrations in childhood cannot be tracked to adulthood with any certainty. In Webber and colleagues’ observational study, half the hypercholesterolaemic children had normal values after 12 years. 4 But let us assume that a screening programme could identify children at high risk only and that a lowering of cholesterol would reduce that risk; the question remains of what to do, because diet is poor as a cholesterol-lowering treatment, particularly in children. Even if diet were efficient as a cholesterollowering treatment, there is no evidence that diet prevents cardiovascular morbidity or mortality. This effect was shown in a systematic review of eight ecological, 41 cross-sectional, 25 cohort, six case-control studies, and a meta-analysis of nine controlled randomised dietary trials. 5 Instead of the prevention of cardiovascular disease, dietary manipulation of healthy children may rather create families of unhappy hypochondriacs, obsessed with their blood chemistry and the composition of their diet. The only way to lower cholesterol concentrations effectively is by drugs. There is no evidence, however, that a possible benefit from cholesterol lowering from a young age may balance possible side-effects from long-term drug use, because luckily, such trials have never been done. I doubt that any parents, with all the facts and assumptions, would allow their child to be screened. Uffe Ravnskov Råbygatan 2, S-22361 Lund, Sweden (e-mail: [email protected]) 1
Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of early lesions in children (FELIC) study. Lancet 1999; 354: 1234–41. 2 Strong JP, Eggen DA, Oalmann MC, Richards ML, Tracy RE. Pathology and epidemiology of atherosclerosis. J Am Diet Assoc 1973; 62: 262–68. 3 Berenson GS, Srinivasan SR. Prevention of atherosclerosis in childhood. Lancet 1999; 354: 1223–24. 4 Webber LS, Srinivasan SR, Wattigney WA, Berenson GS. Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study. Am J Epidemiol 1991; 133: 884–99. 5 Ravnskov U. The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998; 51: 443–60.
Digoxin and heart failure Sir—I am surprised about the publication of S J Lindsay and colleagues’ (Sept 18, p 1003) 1 study on digoxin and mortality in chronic heart failure. Surely, when we already have a prospective, randomised, placebocontrolled trial of digoxin in 6800 patients with heart failure,2 we should not be concerned with a retrospective analysis of a non-randomised cohort of 484 patients? The Digitalis Investigation Group showed that digoxin has no effect, beneficial or adverse, on all-cause mortality in heart failure.2 Lindsay and colleagues’ report in no way alters this conclusion. Although it is undoubtedly true that -blockers and spironolactone are of proven benefit in heart failure, they were tested as adjunctive therapies to digoxin. Furthermore, improving survival is not the only aim of the treatment of heart failure. Digoxin improves symptoms and reduces hospital admissions, both important therapeutic objectives in this disabling and deadly syndrome. John McMurray MRC Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, UK (e-mail: [email protected]) 1
2
Lindsay SJ, Kearney MT, Prescott RJ, Fox KAA, Noland J, UK Heart Investigation. Digoxin and mortality in chronic heart failure. Lancet 1999; 354: 1003. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33.
Authors’ reply Sir—Despite the results of the Digitalis Investigation Group study, 1 many clinicians remain very concerned about the use of digoxin for patients with chronic heart failure who are in sinus rhythm.2 The purpose of our research letter was to present important data about the relation between digoxin and mortality in patients managed in routine clinical practice, with the aim of re-opening the debate in this contentious area. In our report, we advised that our results should be interpreted with caution. However, we believe that our interpretation of the UK-HEART study data is compatible with the results of the Digitalis Investigators Group trial. The results of this study show that the overall neutral mortality effect is achieved by virtue of a finely balanced relation between advantageous and adverse mortality effects of digoxin.2 Furthermore, the adverse mortality effects predominate
69
are
of
greater
*Fekri Abroug, Souheil ElAtrous, Semir Nouira, Habib Haguiga, Slah Bouchoucha *Intensive Care Unit, CHU F Bourguiba, Monastir Emergency Department, 5000 Monastir, Tunisia; and Hôpital Régional Tozeur, Tunisia (e-mail: [email protected]) 1
Abroug F, Nouira S, Haguiga H, et al. A randomised clinical trial of high-dose hydrocortisone hemisuccinate in scorpion envenomation. Ann Emerg Med 1997; 30: 245–58. 2 Ismail M, Fatani AJY, Dabees TT. Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallicrein-kinin inhibitors. Toxicon 1992; 30: 1257–79. 3 Tarasiuk A, Khvatskin S, Sofer S. Effects of antivenom serotherapy on hemodynamic pathophysiology in dogs injected with L quiquistriatus scorpion venom. Toxicon 1998; 36: 963–71. 4 Krifi MN, Elayeb M, Dellagi K. New procedures and parameters for better evaluation of Androctonus australis garzonii (Aag) and Buthus occitanus tunetanus (Bot) scorpion envenomation and specific serotherapy treatment. Toxicon 1996; 34: 257–66. 5 Abraham E. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med 1999; 25: 556–66.
Cushing’s disease Sir—Shinichi Kawai and colleagues (Sept 11, p 951) 1 correctly indicate the efficacy and tolerability of long-term low-dose mitotane in the control of cortisol production in patients with Cushing’s disease who are waiting for pituitary radiotherapy to reduce corticotropin drive. However, they do not mention that mitotane uniformly increases circulating cholesterol concentrations. We studied 21 patients with corticotropin-dependent Cushing’s syndrome treated for up to 77 months and assessed the mechanism of the hypercholesterolaemia. In all patients total serum cholesterol rose on initiation of mitotane therapy by a mean 68% (range 24–196), mainly by increasing LDL cholesterol. The mechanism of increase seemed to be mitotane inhibition of cytochrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for downregulating cholesterol synthesis. Treatment with simvastatin, an inhibitor of cholesterol synthesis, reversed the hyperlipidaemia.2,3 Serum cholesterol is raised in untreated Cushing’s syndrome4 and cardiovascular events are the main cause of the excess mortality associated with this serious condition. 5 Long-term
68
mitotane therapy may control circulating cortisol concentrations, but is unlikely to reduce the risk of cardiovascular events if hypercholesterolaemia is induced and left untreated.
disease because of its sufficient efficacy and lower risk. Shinichi Kawai Institute of Medical Science, St Marianna University School of Medicine, Miyamae-ku, Kawasaki 216-8512, Japan (e-mail: [email protected])
*Peter J Trainer, Michael Besser *Department of Endocrinology, Christie Hospital, Manchester M20 4BX, UK; and Department of Endocrinology, St Bartholomew’s Hospital, London (e-mail: [email protected]) 1
Kawai S, Ichikawa Y, Kaburaki J, Yoshida T. 18 years mitotane therapy for intractable Cushing’s disease. Lancet 1999; 354: 951. 2 Trainer PJ, Howlett TA, Besser GM. The medical management of Cushing’s syndrome using drugs acting on the adrenal cortex. In: Casanueva FF, Dieguez C, eds. Recent advances in basic and clinical neuroendocrinology. Amsterdam: Elsevier Science, 1989: 341–49. 3 Maher VMG, Trainer PJ, Scoppola A, Anderson JV, Thompson GR, Besser GM. Possible mechanism and treatment of o,p⬘DDD-induced hypercholesterolaemia. QJM 1992; 84: 671–79. 4 Taskinen M-R, Nikkila EA, Pelkonen R, Sane T. Plasma lipoproteins, lipolytic enzymes, and very low density lipoprotein triglyceride turnover in Cushing’s syndrome. J Clin Endocrinol Metab 1983; 57: 619–26. 5 Welbourn RB, Montgomery DA, Kennedy TL. The natural history of treated Cushing’s syndrome. Br J Surg 1971; 58: 1–16.
Author’s reply Sir—The serum total cholesterol concentration is increased by mitotane, as Peter Trainer and Michael Besser, and Luton and colleagues1 mention. Concentration initially increased to 8·71 mmol/L in our patient, but gradually decreased even though mitotane therapy was continued. The prognosis of untreated Cushing’s syndrome is poor, with the main causes of death being overwhelming infection and the consequences of hypertension or arteriosclerosis.2 Serious arteriosclerotic complications, such as cardiovascular events, may be explained by several coronary risk factors, including increased serum total or LDL cholesterol, hypertension, obesity, and glucose intolerance caused by hypercortisolaemia. When mitotane therapy is successful, risk of infection and coronary risk factors, except for transient hypercholesterolaemia, may decline. Even if a high serum cholesterol concentration persists, simvastatin or other statins may reverse it, as Trainer and Besser mention. This drug may suppress not only adrenal cortisol production, but also pituitary corticotropin secretion. Thus, longterm mitotane therapy is probably a good choice for intractable Cushing’s
1
Luton JP, Mahoudeau JA, Bouchard P, et al. Treatment of Cushing’s disease by O,p⬘DDD: survey of 62 cases. N Engl J Med 1979; 300: 459–64. 2 Christy NP, ed. Cushing’s syndrome: the natural disease. In: The human adrenal cortex. New York: Harper and Row, 1971: 359–94.
Polycystic ovaries Sir—In Adam Balen’s Sept 18 commentary,1 the reader is left with the impression that hyperinsulinaemia in polycystic ovary syndrome (PCOS) is a consequence of abnormal insulin gene expression rather than a compensatory response to peripheral insulin resistance. As Balen points out, the molecular events underlying PCOS remain unclear. However, hyperinsulinaemia, which exacerbates overproduction of ovarian androgens, is widely believed to occur as a result of peripheral insulin resistance. Studies to assess insulin resistance in women with PCOS by use of the hyperinsulinaemic euglycaemic clamp technique show a 30–40% decrease in insulin-mediated glucose disposal, similar in size to that seen in type 2 diabetes mellitus. 2 Insulin resistance is also seen ex vivo: adipocytes from women with PCOS show decreased insulin sensitivity and responsiveness to glucose uptake. 2 Resistance to insulin manifests itself as an increase in the prevalence of type 2 diabetes: 15% in postmenopausal women with PCOS versus 2·3% in controls matched by age and bodymass index.3 Importantly, insulin-receptormediated effects on ovarian steroidogenesis seem to be preserved in PCOS despite profound resistance to insulinmediated glucose uptake in other tissues, in that there is a selective defect of metabolic as opposed to mitogenic signalling pathways.4 Thus, the beneficial effects of drugs such as metformin and troglitazone2 (which have direct and indirect effects on peripheral carbohydrate metabolism) can be explained by reductions in compensatory insulin secretion by the pancreatic -cell. Such effects indicate that insulin resistance plays a primary pathophysiological role in PCOS, rather than being secondary to androgen excess. Because peripheral insulin resistance in PCOS may be associated with
THE LANCET • Vol 355 • January 1, 2000
premature cardiovascular disease (as in other disease states), resistance to insulin action in vascular tissue, which may be associated with endothelial dysfunction, is an important area of investigation. *Chris Kelly, John Petrie, Helen Lyall, Gwyn Gould, John Connell *Department of Medicine and Therapeutics, University of Glasgow, Glasgow G11 6NT, UK: Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary, Glasgow; and Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Science, University of Glasgow, Glasgow 1
Balen A. Pathogenesis of polycystic ovary syndrome—the enigma unravels? Lancet 1999; 354: 966–67. 2 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implication for pathogenesis. Endocr Rev 1997; 18: 774–800. 3 Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992; 57: 505–13. 4 Book C-B, Danaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999; 84: 3110–16.
Prevention of atherosclerosis in children Sir—Claudio Napoli and colleagues’ (Oct 9, p 1234)1 observation that children from hypercholesterolaemic mothers had more fatty streaks than children from normocholesterolaemic mothers is interesting, but their interpretation of the finding does not agree with present knowledge, or common sense. If the fatty streaks were early atherosclerotic lesions, why were they more common in the fetuses than in the children? Fatty streaks are found worldwide in almost all children, equally often in countries where atherosclerosis is rare, as in countries where it is frequent.2 The development of raised lesions later in life in some individuals must therefore be due to factors other than the mere presence of fatty streaks. Even if we assume that fatty streaks are the forerunners of raised lesions, there is no evidence for blaming a high maternal cholesterol concentration or atherogenic genes; the difference in streak frequency may be due to any hereditary or environmental factor associated with high cholesterol concentrations. To use Napoli and colleagues’ findings as an argument for cholesterol concentration lowering in childhood, as did Berenson and Srinivasan in their commentary,3 seems unfounded. As Napoli and colleagues emphasise, cholesterol concentration was normal
THE LANCET • Vol 355 • January 1, 2000
and similar in both groups, and the fatty streaks cannot therefore have been caused by high concentrations in the child. Even if the fatty streaks had been caused by high concentrations, the predictive value of cholesterol screening is low because concentrations in childhood cannot be tracked to adulthood with any certainty. In Webber and colleagues’ observational study, half the hypercholesterolaemic children had normal values after 12 years. 4 But let us assume that a screening programme could identify children at high risk only and that a lowering of cholesterol would reduce that risk; the question remains of what to do, because diet is poor as a cholesterol-lowering treatment, particularly in children. Even if diet were efficient as a cholesterollowering treatment, there is no evidence that diet prevents cardiovascular morbidity or mortality. This effect was shown in a systematic review of eight ecological, 41 cross-sectional, 25 cohort, six case-control studies, and a meta-analysis of nine controlled randomised dietary trials. 5 Instead of the prevention of cardiovascular disease, dietary manipulation of healthy children may rather create families of unhappy hypochondriacs, obsessed with their blood chemistry and the composition of their diet. The only way to lower cholesterol concentrations effectively is by drugs. There is no evidence, however, that a possible benefit from cholesterol lowering from a young age may balance possible side-effects from long-term drug use, because luckily, such trials have never been done. I doubt that any parents, with all the facts and assumptions, would allow their child to be screened. Uffe Ravnskov Råbygatan 2, S-22361 Lund, Sweden (e-mail: [email protected]) 1
Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of early lesions in children (FELIC) study. Lancet 1999; 354: 1234–41. 2 Strong JP, Eggen DA, Oalmann MC, Richards ML, Tracy RE. Pathology and epidemiology of atherosclerosis. J Am Diet Assoc 1973; 62: 262–68. 3 Berenson GS, Srinivasan SR. Prevention of atherosclerosis in childhood. Lancet 1999; 354: 1223–24. 4 Webber LS, Srinivasan SR, Wattigney WA, Berenson GS. Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study. Am J Epidemiol 1991; 133: 884–99. 5 Ravnskov U. The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998; 51: 443–60.
Digoxin and heart failure Sir—I am surprised about the publication of S J Lindsay and colleagues’ (Sept 18, p 1003) 1 study on digoxin and mortality in chronic heart failure. Surely, when we already have a prospective, randomised, placebocontrolled trial of digoxin in 6800 patients with heart failure,2 we should not be concerned with a retrospective analysis of a non-randomised cohort of 484 patients? The Digitalis Investigation Group showed that digoxin has no effect, beneficial or adverse, on all-cause mortality in heart failure.2 Lindsay and colleagues’ report in no way alters this conclusion. Although it is undoubtedly true that -blockers and spironolactone are of proven benefit in heart failure, they were tested as adjunctive therapies to digoxin. Furthermore, improving survival is not the only aim of the treatment of heart failure. Digoxin improves symptoms and reduces hospital admissions, both important therapeutic objectives in this disabling and deadly syndrome. John McMurray MRC Clinical Research Initiative in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, UK (e-mail: [email protected]) 1
2
Lindsay SJ, Kearney MT, Prescott RJ, Fox KAA, Noland J, UK Heart Investigation. Digoxin and mortality in chronic heart failure. Lancet 1999; 354: 1003. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33.
Authors’ reply Sir—Despite the results of the Digitalis Investigation Group study, 1 many clinicians remain very concerned about the use of digoxin for patients with chronic heart failure who are in sinus rhythm.2 The purpose of our research letter was to present important data about the relation between digoxin and mortality in patients managed in routine clinical practice, with the aim of re-opening the debate in this contentious area. In our report, we advised that our results should be interpreted with caution. However, we believe that our interpretation of the UK-HEART study data is compatible with the results of the Digitalis Investigators Group trial. The results of this study show that the overall neutral mortality effect is achieved by virtue of a finely balanced relation between advantageous and adverse mortality effects of digoxin.2 Furthermore, the adverse mortality effects predominate
69