- Email: [email protected]
WOSCOPS
T H E LANCET Stevens RG, Graubaard BI, Micozzi MS, Neriishi I<, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer 1994; 53: 364-69. 4 Marcus AJ. Aspirin as prophylaxis against colorectal cancer. N EnglJMed 1995; 333: 656-58. 5 Symmons DPM. Safety profile of low-dose aspirin. Lancet 1996; 348: 1394-95. 3
SIR-The winter excess in thrombosisrelated conditions is probably now at its peak, straining primary care and hospital resources. Overviews of trials have given unequivocal evidence of effective prophylaxis from low-dose aspirin. What seems not to be adequately appreciated is the fact that protection is greatest in those patients who receive aspirin early after the onset of symptoms.’sz It would seem reasonable for patients judged at highrisk of myocardial infarction or stroke to be advised to carry an aspirin tablet to be taken immediately chest pain or symptoms suggestive of a cerebral thrombosis are experienced. Indeed, one pharmaceutical firm has produced a pleasant, foil-packed, chewable aspirin tablet which is ideal for carrying in a pocket. Peter Elwood University of Wales College of Medicine, Centre for Applied Public Health Medicine, Cardiff CF1 3NW, UK
1 ISIS-2 Collaborative Group. Randomised
trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 2 Brecker SJD. Early aspirin in myocardial infarction. Lancet 1990; 335: 923.
Oestrogen replacement in prevention of coronary heart disease SIR-The foreword to The Lancet supplement on coronary heart disease (Nov, 1996)’ stated that the publication aimed to reflect “new avenues of understanding”; omission of any mention of oestrogen, and its relation to coronary heart disease in women, is therefore puzzling. Although oestrogen replacement therapy in postmenopausal women has not been evaluated in a randomised controlled trial, there is clinical and epidemiological evidence suggestive of a protective effect of such therapy against coronary heart disease.2There may well be a healthy user effect, leading to overestimation of benefit in observational studies, but this is unlikely to account for all of the protection seen. The effects of oestrogen on lipoprotein cholesterol are well documented, and it has been recommended as first-line
432
therapy for certain postmenopausal hyperlipidaemic women.’ Reduction in the oxidation of low-density lipoprotein cholesterol, and in concentrations of lipoprotein (a), are further consequences of oestrogen replacement. At least as important may be the non-lipid effects of oestrogen. The hormone can increase production of prostaglandin I2 in vascular endothelium, and modulate the acetylcholine-induced response in animal and human coronary arteries. Inotropic changes have also been reported with oestrogen therapy in postmenopausal women. Finally, there are data suggesting an important role for oestrogen replacement in the secondary prevention of coronary heart disea~e.~ M Milner, *P McKenna The Rotunda Hospital, Dublin, Ireland
1 Coronary heart disease. Lancet 1996; 348
(suppl l):.iv. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative review of the epidemiologic evidence. Prev Med 199 1; 20: 47-63. 3 Expert panel on detection, evaluation, and treatment of high cholesterol in adults. Summary of the second report of the National Cholesterol Education Programme (NCEP). J A M 1993; 269: 3015-23. 4 Sullivan JM. Hormone replacement therapy and cardiovascular disease: the human model. Br J Obstet Gynaecoll996; 103: ~59-~67. 2
woscoPs SIR-The West of Scotland Coronary Prevention Group (Nov 16, p 1339)) purports to have performed a subgroup analysis of placebo-treated men in the WOSCOPS population for the purpose of determining which risk factors are associated with the highest absolute risk of coronary heart disease (CHD). The investigators are to be commended for their efforts to provide this relevant information to practising clinicians, who are faced with the decision of which patients to place on lipidlowering therapy. Unfortunately, the data presented do not provide the necessary information. In the Results section they state “men aged 45-54 years who had minor ECG [electrocardiogram] abnormalities, preexisting vascular disease, or who were current smokers had event rates of more than 10% at 5 years”. These data are shown in table I, which lists individual risk factors as if they were analysed separately, revealing the 10.1% event rate associated with smoking in men aged 45-54 years (the highest among the various risk factors other than preexisting vascular disease and ECG
abnormalities). Among men aged 55-64 years, the table implies that each risk factor listed (other than isolated hypercholesterolaemia) is associated with an event rate greater than 10% over 5 years. Indeed, the trialists seem to have inadvertently accepted this invalid conclusion themselves by elaborating in their Discussion “subgroup analysis of WOSCOPS shows a 5-year absolute event risk of more than 10% in men aged 45-64 years with moderate hypercholesterolaemia and vascular disease, and in men aged 55-64 years with at least one risk factor. These men are, therefore, candidates for vigorous risk-factor management including drug treatment”. Further conclusions are based on the spurious event rate of 10.1% in men younger than 55 years who smoked, specifically that “such individuals should be advised to stop smoking, but lipid-lowering drug therapy could be considered if they were unable to do so”. Upon closer inspection however, the fine print under table 1 tells us that “there were insufficient endpoints to allow exclusive analysis” for risk factors other than isolated hypercholesterolaemia, and that the “smoking category includes all smokers, some of whom will have other risk factors”. I agree with the WOSCOPS investigators that men whose 5-year risk of a major coronary event equals or exceeds 10% are candidates for lipidlowering drug therapy, whether for primary or secondary prevention of CHD, but without separate analysis of each individual risk factor, we still do not b o w whether this target group includes men aged 55-64 years with one risk factor, much less men under 55 years who continue to smoke. Thomas A Barringer 111 Carolinas Medical Center, Department of Family Practice, Charlotte NC 28232-2861, USA
1 West of Scotlaud Coronary Prevention
Group. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996; 345: 133942.
Authors‘ reply SIR-Bairinger is right to point out that our analysis of risk in table 1 was exclusive for isolated hypercholesterolaemia and inclusive for the other vascular risk factors. This point was also raised by one of the referees of the paper and is a drawback of subgroup analysis, although not a fatal one. There were, of course, too few endpoints to allow exclusive analyses in all the subgroups. If we take men aged 45-54 years with hypercholesterolaemia
-
Vo1349 February 8, 1997
THE LANCET
and a family history of premature vascular disease but nothing else-ie, nonsmoking, normotensive with highdensity liporotein greater than 1.1 nmoliL, normal electrocardiogram (ECG), and no clinical evidence of vascular disease-we end up with 28 men and one event in the placebo group, and with 23 men and no events in the pravastatin group. For this reason we felt that we were obliged to conduct an inclusive analysis, with the important exception of isolated hypercholesterolaemia. T o have analysed our data exclusively would have meant an impossibly wide confidence interval. An alternative approach to the study of the role of a large number of risk factors is to use more complex statistical modelling. A multivariate analysis of the WOSCOPS data will shortly appear.’ A related point is that the data we published will only apply to a high-risk population such as that found in the west of Scotland and northern and eastern Europe. Fewer men living in southern England, France, Spain, and Italy will have cardiovascular event rates that exceed 10% over 5 years, even when additional risk factors are present. It would seem sensible therefore to recommend that individual countries draw up guidelines for drug treatment t h a t are based on the coronary heart disease (CHD) rates prevalent in each country at the time. As a result of our analysis of the WOSCOPS data, we are on much more certain ground with respect to the risk of vascular disease in the west of Scotland than we were before, when we had to rely on estimates of risk derived from other publications, notably that of Framingham. On balance we feel that the advantages associated with this new level of certainty outweigh Barringer’s fears about the inclusive or exclusive analysis of the data. The main conclusions of our report are that individuals with no risk factors other than mild hypercholesterolaemia have a low risk of a major CHD event over 5 years, and might therefore not merit the use of an expensive treatment, whereas possession of at least one additional risk factor is an indication for more aggressive investigation and assessment. The absolute benefits of treating at-risk middle-aged men with hypercholesterolaemia are less than for treatment of men with established CHD, but greater than the benefits of treating mild hypertension in men of similar age to reduce the risk of stroke. *Christopher Isles, Stuart Cobbe, /an Ford, on behalf of the West of Scotland Coronary Prevention Study Group *Department of Medicine, Dumiries and Galloway Royal Infirmary, Dumiries D G I 4AP, UK; Department o i Medical Cardiology, Royal Iniirmary, Glasgow; Robertson Centre for Biostatistics, University o i Glasgow, UK
Vol349 *February 8,1997
1 West of Scotland Coronary Prevention Study Group. Baseline risk factors and their association with outcome in West of Scotland Coronary Prevention Study. A m J Cardzol (in press).
Feeding tubes in prevention of pneumonia SIR-Finucane and Bynum (Nov 23, p 1421)’ report that feeding tubes do not reduce the risk of aspiration pneumonia in patients with neurogenic dysphagia. But why should feeding tubes do so? I believe that this is a false premise. After all, the purpose of a feeding tube is to feed the patient: no more, no less. With data gathered at these workers’ institution, we showed that aspiration is much less common in intensive care units (ICUs) (0.9% of patients aspirated during 6 months of observation) than on the wards (4.2% probability) . z Clearly, the combination of intensive nursing and the presence of endotracheal tubes prevented aspiration, despite the greater clinical acuity of the ICU patients. Patients who are prone to aspiration will do SO even if they are unfed, but surely Finucane and Bynum do not advocate starvation as a therapeutic option. Total parenteral nutrition, which they offer as an alternative, is not realisticon both financial and physiological grounds. Hand feeding, another alternative they suggest, unfortunately is also extremely expensive because it requires a large staff whose time is dedicated to this slow and difficult task. Such funding is not available in any acute or long-term care setting in the USA. Although some patients may have a dedicated family who can do this task, many will not. The real solution, I believe, is a randomised, controlled trial of jejunostomy versus gastrostomy. Unfortunately, I fear the conclusion that many readers will take from Finucane and Bynum’s report is tht feeding tubes are dangerous, uncomfortable, and best avoided. The same may be said of starvation. Such a take-home lesson would be a true disservice, because it would set back the gains that have slowly been made by clinical nutritionists in educating physicians about the importance of feeding their patients.
Presentation of Whipple’s disease SIR-Bowles and colleagues (Nov 16, p 1356)’ emphasise that Whipple’s disease is a systemic disorder and that most doctors are unfamiliar with the range of presentations. We have seen a patient with an unusual diagnostic finding of Whipple’s disease. A severely ill, 65-year-old man presented with malaise, an 8-week history of watery diarrhoea, dysphagia, anorexia, and 7-kg weight loss. He had had arthralgia and myalgia and fever with chills every day. There was an exertional dyspnoea and he had become bedridden. In the previous 2 years he had been extensively investigated for fever of unknown origin, arthritis, stiffness of shoulder and hip musculature, dyspnoea, hypercalcaemia, and leucocytosis. However, a firm diagnosis could not be established. During these 2 years he had been treated with prednisone (5-20 mg daily). A whole-body 67galliumcitrate scan was done and this showed a diffuse increased accumulation of the tracer (figure). Full-thickness biopsy of skin, fascia, and muscle was done which showed polymyositis. However, the fever, diarrhoea, weight loss, and arthralgia also suggested Whipple’s disease, which was confirmed by jejunal biopsies. Muscle biopsy was additionally stained with periodic acidSchiff (PAS) and revealed PASpositive, diastase-resistant material in the infiltrate. Electron microscopic studies of the muscle biopsy specimen
*Ronenn Roubenoff, Jean Mayer *United States Department of Agriculture, Human Nutrltion Research Center on Aging, Tufts University, Boston, MA 02111, USA; and New England Medical Center, Boston
1 Finucane TE, Bynum JPW. Use of tube feeding to prevent aspiration pneumonia. Lancet 1996; 348: 1421-24. 2 Mullan H, Roubenoff RA, Roubenoff R. Risk of pulmonary aspiration among patients receiving enteral nutrition support. J Parent Enteral Nutr 1992; 16: 160-64.
A 67gallium-citratescan of a patient with Whipple’s disease (anterior view)
433
SIR-The winter excess in thrombosisrelated conditions is probably now at its peak, straining primary care and hospital resources. Overviews of trials have given unequivocal evidence of effective prophylaxis from low-dose aspirin. What seems not to be adequately appreciated is the fact that protection is greatest in those patients who receive aspirin early after the onset of symptoms.’sz It would seem reasonable for patients judged at highrisk of myocardial infarction or stroke to be advised to carry an aspirin tablet to be taken immediately chest pain or symptoms suggestive of a cerebral thrombosis are experienced. Indeed, one pharmaceutical firm has produced a pleasant, foil-packed, chewable aspirin tablet which is ideal for carrying in a pocket. Peter Elwood University of Wales College of Medicine, Centre for Applied Public Health Medicine, Cardiff CF1 3NW, UK
1 ISIS-2 Collaborative Group. Randomised
trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 2 Brecker SJD. Early aspirin in myocardial infarction. Lancet 1990; 335: 923.
Oestrogen replacement in prevention of coronary heart disease SIR-The foreword to The Lancet supplement on coronary heart disease (Nov, 1996)’ stated that the publication aimed to reflect “new avenues of understanding”; omission of any mention of oestrogen, and its relation to coronary heart disease in women, is therefore puzzling. Although oestrogen replacement therapy in postmenopausal women has not been evaluated in a randomised controlled trial, there is clinical and epidemiological evidence suggestive of a protective effect of such therapy against coronary heart disease.2There may well be a healthy user effect, leading to overestimation of benefit in observational studies, but this is unlikely to account for all of the protection seen. The effects of oestrogen on lipoprotein cholesterol are well documented, and it has been recommended as first-line
432
therapy for certain postmenopausal hyperlipidaemic women.’ Reduction in the oxidation of low-density lipoprotein cholesterol, and in concentrations of lipoprotein (a), are further consequences of oestrogen replacement. At least as important may be the non-lipid effects of oestrogen. The hormone can increase production of prostaglandin I2 in vascular endothelium, and modulate the acetylcholine-induced response in animal and human coronary arteries. Inotropic changes have also been reported with oestrogen therapy in postmenopausal women. Finally, there are data suggesting an important role for oestrogen replacement in the secondary prevention of coronary heart disea~e.~ M Milner, *P McKenna The Rotunda Hospital, Dublin, Ireland
1 Coronary heart disease. Lancet 1996; 348
(suppl l):.iv. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative review of the epidemiologic evidence. Prev Med 199 1; 20: 47-63. 3 Expert panel on detection, evaluation, and treatment of high cholesterol in adults. Summary of the second report of the National Cholesterol Education Programme (NCEP). J A M 1993; 269: 3015-23. 4 Sullivan JM. Hormone replacement therapy and cardiovascular disease: the human model. Br J Obstet Gynaecoll996; 103: ~59-~67. 2
woscoPs SIR-The West of Scotland Coronary Prevention Group (Nov 16, p 1339)) purports to have performed a subgroup analysis of placebo-treated men in the WOSCOPS population for the purpose of determining which risk factors are associated with the highest absolute risk of coronary heart disease (CHD). The investigators are to be commended for their efforts to provide this relevant information to practising clinicians, who are faced with the decision of which patients to place on lipidlowering therapy. Unfortunately, the data presented do not provide the necessary information. In the Results section they state “men aged 45-54 years who had minor ECG [electrocardiogram] abnormalities, preexisting vascular disease, or who were current smokers had event rates of more than 10% at 5 years”. These data are shown in table I, which lists individual risk factors as if they were analysed separately, revealing the 10.1% event rate associated with smoking in men aged 45-54 years (the highest among the various risk factors other than preexisting vascular disease and ECG
abnormalities). Among men aged 55-64 years, the table implies that each risk factor listed (other than isolated hypercholesterolaemia) is associated with an event rate greater than 10% over 5 years. Indeed, the trialists seem to have inadvertently accepted this invalid conclusion themselves by elaborating in their Discussion “subgroup analysis of WOSCOPS shows a 5-year absolute event risk of more than 10% in men aged 45-64 years with moderate hypercholesterolaemia and vascular disease, and in men aged 55-64 years with at least one risk factor. These men are, therefore, candidates for vigorous risk-factor management including drug treatment”. Further conclusions are based on the spurious event rate of 10.1% in men younger than 55 years who smoked, specifically that “such individuals should be advised to stop smoking, but lipid-lowering drug therapy could be considered if they were unable to do so”. Upon closer inspection however, the fine print under table 1 tells us that “there were insufficient endpoints to allow exclusive analysis” for risk factors other than isolated hypercholesterolaemia, and that the “smoking category includes all smokers, some of whom will have other risk factors”. I agree with the WOSCOPS investigators that men whose 5-year risk of a major coronary event equals or exceeds 10% are candidates for lipidlowering drug therapy, whether for primary or secondary prevention of CHD, but without separate analysis of each individual risk factor, we still do not b o w whether this target group includes men aged 55-64 years with one risk factor, much less men under 55 years who continue to smoke. Thomas A Barringer 111 Carolinas Medical Center, Department of Family Practice, Charlotte NC 28232-2861, USA
1 West of Scotlaud Coronary Prevention
Group. West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996; 345: 133942.
Authors‘ reply SIR-Bairinger is right to point out that our analysis of risk in table 1 was exclusive for isolated hypercholesterolaemia and inclusive for the other vascular risk factors. This point was also raised by one of the referees of the paper and is a drawback of subgroup analysis, although not a fatal one. There were, of course, too few endpoints to allow exclusive analyses in all the subgroups. If we take men aged 45-54 years with hypercholesterolaemia
-
Vo1349 February 8, 1997
THE LANCET
and a family history of premature vascular disease but nothing else-ie, nonsmoking, normotensive with highdensity liporotein greater than 1.1 nmoliL, normal electrocardiogram (ECG), and no clinical evidence of vascular disease-we end up with 28 men and one event in the placebo group, and with 23 men and no events in the pravastatin group. For this reason we felt that we were obliged to conduct an inclusive analysis, with the important exception of isolated hypercholesterolaemia. T o have analysed our data exclusively would have meant an impossibly wide confidence interval. An alternative approach to the study of the role of a large number of risk factors is to use more complex statistical modelling. A multivariate analysis of the WOSCOPS data will shortly appear.’ A related point is that the data we published will only apply to a high-risk population such as that found in the west of Scotland and northern and eastern Europe. Fewer men living in southern England, France, Spain, and Italy will have cardiovascular event rates that exceed 10% over 5 years, even when additional risk factors are present. It would seem sensible therefore to recommend that individual countries draw up guidelines for drug treatment t h a t are based on the coronary heart disease (CHD) rates prevalent in each country at the time. As a result of our analysis of the WOSCOPS data, we are on much more certain ground with respect to the risk of vascular disease in the west of Scotland than we were before, when we had to rely on estimates of risk derived from other publications, notably that of Framingham. On balance we feel that the advantages associated with this new level of certainty outweigh Barringer’s fears about the inclusive or exclusive analysis of the data. The main conclusions of our report are that individuals with no risk factors other than mild hypercholesterolaemia have a low risk of a major CHD event over 5 years, and might therefore not merit the use of an expensive treatment, whereas possession of at least one additional risk factor is an indication for more aggressive investigation and assessment. The absolute benefits of treating at-risk middle-aged men with hypercholesterolaemia are less than for treatment of men with established CHD, but greater than the benefits of treating mild hypertension in men of similar age to reduce the risk of stroke. *Christopher Isles, Stuart Cobbe, /an Ford, on behalf of the West of Scotland Coronary Prevention Study Group *Department of Medicine, Dumiries and Galloway Royal Infirmary, Dumiries D G I 4AP, UK; Department o i Medical Cardiology, Royal Iniirmary, Glasgow; Robertson Centre for Biostatistics, University o i Glasgow, UK
Vol349 *February 8,1997
1 West of Scotland Coronary Prevention Study Group. Baseline risk factors and their association with outcome in West of Scotland Coronary Prevention Study. A m J Cardzol (in press).
Feeding tubes in prevention of pneumonia SIR-Finucane and Bynum (Nov 23, p 1421)’ report that feeding tubes do not reduce the risk of aspiration pneumonia in patients with neurogenic dysphagia. But why should feeding tubes do so? I believe that this is a false premise. After all, the purpose of a feeding tube is to feed the patient: no more, no less. With data gathered at these workers’ institution, we showed that aspiration is much less common in intensive care units (ICUs) (0.9% of patients aspirated during 6 months of observation) than on the wards (4.2% probability) . z Clearly, the combination of intensive nursing and the presence of endotracheal tubes prevented aspiration, despite the greater clinical acuity of the ICU patients. Patients who are prone to aspiration will do SO even if they are unfed, but surely Finucane and Bynum do not advocate starvation as a therapeutic option. Total parenteral nutrition, which they offer as an alternative, is not realisticon both financial and physiological grounds. Hand feeding, another alternative they suggest, unfortunately is also extremely expensive because it requires a large staff whose time is dedicated to this slow and difficult task. Such funding is not available in any acute or long-term care setting in the USA. Although some patients may have a dedicated family who can do this task, many will not. The real solution, I believe, is a randomised, controlled trial of jejunostomy versus gastrostomy. Unfortunately, I fear the conclusion that many readers will take from Finucane and Bynum’s report is tht feeding tubes are dangerous, uncomfortable, and best avoided. The same may be said of starvation. Such a take-home lesson would be a true disservice, because it would set back the gains that have slowly been made by clinical nutritionists in educating physicians about the importance of feeding their patients.
Presentation of Whipple’s disease SIR-Bowles and colleagues (Nov 16, p 1356)’ emphasise that Whipple’s disease is a systemic disorder and that most doctors are unfamiliar with the range of presentations. We have seen a patient with an unusual diagnostic finding of Whipple’s disease. A severely ill, 65-year-old man presented with malaise, an 8-week history of watery diarrhoea, dysphagia, anorexia, and 7-kg weight loss. He had had arthralgia and myalgia and fever with chills every day. There was an exertional dyspnoea and he had become bedridden. In the previous 2 years he had been extensively investigated for fever of unknown origin, arthritis, stiffness of shoulder and hip musculature, dyspnoea, hypercalcaemia, and leucocytosis. However, a firm diagnosis could not be established. During these 2 years he had been treated with prednisone (5-20 mg daily). A whole-body 67galliumcitrate scan was done and this showed a diffuse increased accumulation of the tracer (figure). Full-thickness biopsy of skin, fascia, and muscle was done which showed polymyositis. However, the fever, diarrhoea, weight loss, and arthralgia also suggested Whipple’s disease, which was confirmed by jejunal biopsies. Muscle biopsy was additionally stained with periodic acidSchiff (PAS) and revealed PASpositive, diastase-resistant material in the infiltrate. Electron microscopic studies of the muscle biopsy specimen
*Ronenn Roubenoff, Jean Mayer *United States Department of Agriculture, Human Nutrltion Research Center on Aging, Tufts University, Boston, MA 02111, USA; and New England Medical Center, Boston
1 Finucane TE, Bynum JPW. Use of tube feeding to prevent aspiration pneumonia. Lancet 1996; 348: 1421-24. 2 Mullan H, Roubenoff RA, Roubenoff R. Risk of pulmonary aspiration among patients receiving enteral nutrition support. J Parent Enteral Nutr 1992; 16: 160-64.
A 67gallium-citratescan of a patient with Whipple’s disease (anterior view)
433