Control of meningococcal disease in west Africa

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The HOPE study and diabetes Sir—The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (Jan 22, p 253)1 report that ramipril given to people with diabetes mellitus lowered the risk of major cardiovascular outcomes by 25–30%. They claim that the effect was apparent irrespective of whether participants had a history of cardiovascular events, hypertension, or microalbuminuria, were taking insulin or oral hypoglycaemic agents, or had type-1 or type-2 diabetes mellitus. The investigators also state that ramipril lowered the risk of overt nephropathy, renal failure, or laser therapy, and that it had no long-term effect on glycaemic control. Although these results are interesting, several critical points can be raised, and it can also be argued that the new information given in the paper is limited. Figure 2 shows that the relative risk reduction in subgroups without microalbuminuria, with no cardiovascular disease and with type-1 diabetes do not reach significance despite high numbers of patients: without microalbuminuria (n=2437) and with no cardiovascular disease (n=1119). Since more than 98% of the patients had type-2 diabetes mellitus it is obvious that no conclusions of the effect of ramipril in type-1 diabetes mellitus can be drawn from the study. Thus, only in patients with diabetes with microalbuminuria or cardiovascular disease, or both, at high risk of having cardiovascular events, is the relative risk reduction significant. No data on metabolic control and blood pressure as absolute figures are given in the paper. We are only told that blood pressure and glycated haemoglobin (HbA1c) are significantly lower in the ramipril group, but for HbA1c the difference is not shown. Thus, it can be argued that the findings in this study only confirm what has been shown in the UK Prospective Diabetes Study.2 In the conclusion the investigators claim that ramipril lowered the risk of nephropathy, renal failure, or laser

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therapy. Ramipril does indeed reduce the risk of developing nephropathy in patients with microalbuminuria, as previous studies have shown. 3 However, table 3 shows that there was no effect on laser therapy (p=0·24) nor dialysis (p=0·70) in the ramipril group. The results of the HOPE study in patients with diabetes mellitus are important but mostly because they confirm previous studies. The study underlines the importance of strict metabolic control and aggressive antihypertensive treatment in highrisk patients with type-2 diabetes who have cardiovascular disease or microalbuminuria. However, it is not shown that patients with uncomplicated type-2 diabetes, with only one additional risk factor, will benefit from angiotensin-convertingenzyme (ACE) inhibitor treatment. Nor is it shown that there are new effects of ACE-inhibitors on end-stage manifestations of diabetic nephropathy or proliferative retinopathy. Tonny Jensen Department of Endocrinology, Hvidovre University Hospital of Copenhagen, DK-2650 Hvidovre, Denmark 1

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Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–59. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–20. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7 year follow-up study. Arch Intern Med 1996; 156: 286–89.

Sir—The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators 1 found that patients treated with the angiotensinconverting-enzyme (ACE) inhibitor ramipril as well as other antihypertensive medications had fewer cardiovascular events, despite a

modest further lowering of blood pressure. How do these findings fit with other trials assessing drugs with antihypertensive and other cardiovascular effects in similar diabetic populations? Consistent results were reported in the Captopril Prevention Project (CAPPP) trial,2 in which cardiovascular events were found to be reduced in patients with diabetes assigned antihypertensive treatment with captopril, compared with patients assigned conventional therapy with diuretics, ␤-blockers, or both. Similarly, in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial3 ACE inhibitors were found to produce better results than calcium-channel blockers in the treatment of patients with diabetes and hypertension. On the other hand, in the UK Prospective Diabetes Study (PDS)4 tight control of blood pressure in patients with diabetes with either captopril or atenolol was found to be better than conventional treatment (not described, except that ACE inhibitors and ␤-blockers were avoided). However, there was no significant difference in outcome between patients randomly assigned captopril and those assigned atenolol. One possible explanation that would reconcile these apparently disparate studies is that both ACE inhibitors and ␤-blockers have specific benefits in patients with diabetes additional to any antihypertensive effect, and that the magnitude of this additional benefit is similar with both groups of drugs. The HOPE study adds to previous data that shows that ACE inhibitors reduce the development and progression of diabetic nephropathy, which in turn is a strong predictor of subsequent macrovascular disease. Although not the explanation for the benefits seen in HOPE, ACE inhibitors also reduce adverse ventricular remodelling in diabetic patients with left venticular dysfunction. When given to diabetic patients after a myocardial infarction, ␤-blockers reduce death and reinfarction. 5 ␤-blockers may be particularly beneficial at reducing

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silent ischaemia or the manifestations of autonomic dysfunction, both of which are common with diabetes. Patients with diabetes may be at a therapeutic disadvantage if they are given drugs used in the control or conventional treatment arms of some studies. In particular, thiazide diuretics may be less effective in those with diabetes (compared with those without diabetes) at lowering blood pressure and may also cause adverse metabolic effects.5 Based on current evidence ACE inhibitors and ␤-blockers should be considered as first-line treatment in patients with diabetes and hypertension, diabetes and coronary disease or, in particular, all three disorders. Although there remain many unanswered questions, there are at last well designed trial data to aid management of a complex patient population at high risk for cardiovascular events. Mark W I Webster Department of Cardiology, Green Lane Hospital, Auckland 3, New Zealand (e-mail: [email protected]) 1

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Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–59. Hansson L, Lindhol LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–16. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–52. UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13. Webster MWI, Scott RS. What cardiologists need to know about diabetes. Lancet 1997; 350 (suppl 1): 23–28.

Sir—To assess the possible impact of the Heart Outcomes Prevention Evaluation (HOPE) study1 in clinical practice, we examined data on 109 consecutive patients over the age of 55 years seen in a single diabetes clinic within a medium-sized district general hospital in the UK. Eight of these patients would have been excluded from the HOPE study because of established proteinuria or renal failure. Of the remaining 101 patients, only 12 did not have at least one additional risk factor for ischaemic heart disease as defined in the HOPE

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Total number of patients Mean age (years) History of hypertension including use of antihypertensives Cholesterol >5·2 mmol/L Current smoker Hypolipidaemic drug use Aspirin use

Royal Glamorgan Hospital

HOPE ramipril arm

101 (8% type 1) 66·2 52% 45% 20% 26% 39%

1808 (2% type 1) 65·3 58% 65% 15% 23% 54%

Characteristics of patients with diabetes in Royal Glamorgan Hospital, Llantrisant, UK, and ramipril arm of HOPE

trial (total cholesterol >5·2 mmol/L, hypertension, smoking, previous cardiovascular event, or microalbuminuria; table). Therefore, 89 patients would have potentially benefited from the use of ramipril but only 33 are currently prescribed an angiotensin-converting-enzyme (ACE) inhibitor (two on ramipril). If the findings of HOPE are implemented it would result in the prescription of ramipril to most middle-aged patients with diabetes. In our clinic population, over 80% would be candidates for the drug but less than 40% are currently taking an ACE inhibitor. In an average sized district general hospital such as ours, the diabetes team provides services to about 1000 patients with diabetes and we might be expected to generate an extra 400 prescriptions for ACE inhibitors at an estimated cost of £91 200 (US$139 536) per annum to the local prescribing budget (assuming a cost of £19 [US$29] per patient/month). Over 4·5 years we would expect to prevent 24 major cardiovascular and microvascular events at a cost less than that of home blood-glucose monitoring strips, which have never been shown to reduce mortality or morbidity in patients with diabetes. V Lewis, P Kloer, N Prasad, *J C Alcolado Department of Medicine, Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant CF72 8XR, UK (e-mail: [email protected]) 1

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–59.

Sir—The HOPE study 1 has major implications for the care of patients with type-2 diabetes. Although the investigators chose to study patients at increased cardiovascular risk by confining recruitment to patients with diabetes and an additional risk factor, we believe this represents most patients with type-2 diabetes. We assessed the potential impact of this study by finding out the number of patients attending primary-care and

secondary-care diabetes clinics who met the trial entry criteria. We used data from paper records of annual review data of 200 consecutive hospital patients and from 390 patients from two general-practice computerised databases. These data sets did not have full information on all the inclusion criteria for the HOPE trial, therefore our numbers will represent an underestimate. On the basis of the inclusion criteria 189 (94·5%) patients in hospital clinics should be on ACE inhibitors whereas only 71 (35·5%) were on an ACE inhibitor. In general practice 322 (82·6%) meet the HOPE criteria (117 [30%] were taking an ACE inhibitor), even though patients with complex medical histories are more likely to be reviewed in hospital. At present only one third of the patients attending either hospital or primary-care diabetes clinics are currently receiving an ACE inhibitor. If the findings of the HOPE study are implemented our clinical practice will have to change because a clear majority of patients with type-2 diabetes who attend diabetes clinics merit treatment with an ACE inhibitor. Nish Chaturvedi, 2 in the accompanying commentary, asks how to treat the patient with diabetes who has normal blood pressure but who has isolated hypercholesterolaemia or smokes. Our survey showed that very few patients reach the Joint National Committee VI guidelines3 target blood pressure of 130/85 mm Hg. This blood pressure was only achieved in 2% of the secondary-care patients and 8% of the primary-care patients we studied. Guidelines on how to treat patients without hypertension, at least as defined by this target level, are not a priority at present. The implementation of the HOPE study findings will have important implications for the funding of primary and secondary health care because type-2 diabetes is common, affecting in excess of 150 million patients worldwide. The expenditure will be justified as the HOPE study shows that we need to treat 15 patients for a mean of 4·5 years to prevent one patient from having a myocardial infarction, or needing a

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revascularisation procedure, laser therapy, or dialysis, or developing overt nephropathy. The drug cost to prevent an individual developing one of these complications is £16 760 and these costs are much less than the health-care and other costs of the associated complications. The HOPE trial has again focused our attention on the interventions available for reducing morbidity in type-2 diabetes. Now, in addition to good glycaemic control, intensive blood pressure, and lipid lowering strategies, most patients with type-2 diabetes will benefit from an ACE inhibitor.

and to even prevent new diabetes in non-diabetic patients needs further study in preferably randomised comparative trials with specific antihypertensive agents (eg, angiotensin II receptor antagonists, urapidil, long-acting calcium channel blockers, ␤1-selective ␤-blockers). *Mike Stubanus, Dierk Endemann, Michael Fischereder, Karl Peter Ittner, Bernhard K Krämer Klinik und Poliklinik für Innere Medizin II und Anästhesiologie, University of Regensburg, D-93042 Regensburg, Germany (e-mail: bernhard [email protected]) 1

*Gerry Fegan, David Ward, Leo Clarke, Kenneth MacLeod, Andrew Hattersley *Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, Exeter EX2 5AX, UK; The Surgery, Honiton, Devon; and Ide Lane Surgery, Alphington, Exeter 1

2

3

Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–59. Chaturvedi N. HOPE and extension of the indications of ACE inhibitors? Lancet 2000; 355: 246–47. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413–46.

Sir—In the study by the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators1 ramipril lowered the risk of overt nephropathy by 24% and lowered the albumin/ creatinine ratio in the affected patients. Furthermore, ramipril treatment prevented a new diagnosis of diabetes in non-diabetic patients by 34%.2 This is in accordance with data from the Captopril Prevention Project (CAPPP) study 3 in which the number of patients newly diagnosed as having diabetes decreased by 11% during captopril treatment. In the HOPE/MICRO-HOPE study 1 ramipril improved glycaemic control as assessed by HbA1c during years 1 and 2 in patients with diabetes. This improved glycaemic control could contribute to the improved cardiovascular and microvascular outcomes. 1,4 Ramipril is known to improve glucose disposal in streptozotocin diabetic rats. 5 Underlying mechanisms may comprise enhanced bradykinin availability with subsequent vasodilation and improved insulin sensitivity in skeletal muscle tissue. The ability of ramipril to improve glycaemic control in diabetic patients

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2

3

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Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–59. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000; 342: 145–53. Hansson L, Lindholm LH, Niskanen L, et al, for the Captopril Prevention Project (CAPPP) study group. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–16. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86. Ittner KP, Zimmerman M, Bucher M, et al. The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 92–97.

Authors’ reply Sir—The HOPE Study was designed to find out if the addition of the angiotensin-converting enzyme (ACE) inhibitor ramipril to the medical regimen of patients at high risk of having cardiovascular events, reduces the risk of such events. For those with diabetes, we ensured that the results would be relevant to individuals at high risk for cardiovascular events by specifying that included individuals had to have at least one other cardiovascular risk factor. We did not design the study to find out whether the intervention was more effective in subgroups of participants with diabetes and certain risk factors, including those with microalbuminuria, a previous history of cardiovascular disease, or other baseline risk factors (eg, hypertension, dyslipidaemia, or smoking). It is important to avoid over-interpreting

the results of any subgroup analysis— they are only presented to illustrate the fact that the results were consistent across subgroups. Indeed, when a study shows a clear overall benefit, the results are applicable to most types of participants studied, unless a significant statistical interaction is shown. No study is designed to provide independent significance in every subgroup of interest. In the HOPE study we showed a clear overall benefit for patients with diabetes who were taking ramipril, this benefit was consistent in those with and without previous cardiovascular disease or microalbuminuria. There was no evidence of statistical heterogeneity for any subgroup. We therefore disagree with Tonny Jensen’s comment: the results are relevant for a broad range of individuals who are at high risk of having cardiovascular events. Jensen is indeed correct to point out that ramipril reduced the risk of the overt nephropathy (a pre-specified outcome of the analysis). This finding therefore extends the results of previous work done in younger, normotensive, microalbuminuric people with type-2 diabetes 1 to a broader group of older, high cardiovascular risk, normotensive, and hypertensive individuals with diabetes with and without microalbuminuria. We combined nephropathy with laser therapy or renal failure (both considered to be signs of microvascular disease) and showed consistent results. We welcome Mark Webster’s comments and would like to emphasise the difficulties inherent in comparing the HOPE study results in the treated hypertensive (56%) and nonhypertensive (44%) subgroups (with a mean blood pressure at entry of 142/80 mm Hg), to the UKPDS study’s results in hypertensive individuals (with a mean blood pressure at entry of 159/94 mm Hg) randomly assigned atenolol or captopril.2 The HOPE study was not a trial of antihypertensive therapy, and no attempt was made to treat blood pressure to any predetermined target. It therefore provides no information on the relative efficacy of one active agent versus another. Instead, it shows that in addition to current care (which may include ␤-blockers, diuretics, or calciumchannel blockers), ramipril effectively reduced the risk of cardiovascular events and nephropathy. Finally, we agree with V Lewis and colleagues, and Gerry Fegan and colleagues that many people with diabetes may expect to benefit from the

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addition of an ACE inhibitor. We also agree with Mike Stubanus and colleagues that the metabolic effects of ramipril and other modulators of the renin-angiotensin system require further study. *Hertzel C Gerstein, Salim Yusuf, on behalf of the HOPE Study Investigators Canadian Cardiovascular Collaboration Project Office, HGH-McMaster Clinic, Barton Street East, Hamilton, Ontario L8L 2X2, Canada (e-mail: [email protected]) 1

2

Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7 year follow-up study. Arch Intern Med 1996; 156: 4286–89. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317: 713–20.

Discontinuation symptoms and psychotropic drugs Sir—The clinical impact of discontinuation symptoms with the selective reuptake inhibitors (SSRIs) has attracted much interest. 1 Discontinuation symptoms were only recognised after the SSRIs had been in widespread clinical use for several years. Initial estimates of prevalence, based on spontaneous adverse drug reaction reports, suggested that such symptoms were a rare occurrence. However, double-blind controlled studies now indicate that 35–78% of patients who abruptly stop certain antidepressants, after several months of treatment, will develop one or more discontinuation symptoms. 2–4 Although the symptoms are varied, and are both physical and psychological, a characteristic SSRI discontinuation syndrome is now recognised. Symptoms are usually mild and transient, but occasionally are of longer duration and cause considerable morbidity. Misdiagnosis can lead to inappropriate treatment and there are implications for how clinicians should end antidepressant treatment and for patients who comply intermittently with medication. Information sheets for several newer antidepressants have been amended to include relevant information. Discontinuation symptoms are not restricted to the SSRIs. Many drugs that act on the central nervous system can cause transient symptoms on sudden stoppage, without evidence of addiction, reflecting adaptation in biological systems5—eg, monoamine

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oxidase inhibitors, tricyclic antidepressants, antiparkinsonian agents, traditional antipsychotics, and clozapine. It would be prudent for the occurrence of discontinuation symptoms to be investigated before licensing. We propose that for all new psychotropic drugs, double-blind efficacy trials incorporate a doubleblind follow-up, of several weeks duration after active drug or placebo is stopped, during which time all new adverse events are monitored. If the underlying psychiatric disorder is serious, and the drug has been effective, this may raise ethical issues but trial design can address these. A placebo arm is essential because placebo discontinuation symptoms can occur. 2,3 If significant discontinuation symptoms are identified, further studies should assess their natural course, the effectiveness of tapering schedules in prevention, treatment options, and whether certain individuals are more susceptible. Such studies should also assess other dimensions of addiction—eg, tolerance, craving, akrasia. 5 Such information will clarify whether discontinuation symptoms are an isolated phenomenon, as is the case with antidepressants and antipsychotics, or one part of a syndrome of addiction/dependence, as may occur with drugs such as the benzodiazepines. A more rigorous approach to the characterisation of discontinuation symptoms will have clinical and research benefits and replace conclusions drawn from sporadic studies and anecdotal reports. Our patients deserve better. *Allan Young, Peter Haddad *Department of Psychiatry, University of Newcastle, The Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; and Department of Psychiatry, Trafford General Hospital, Davyhulme, Manchester, UK 1

2

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Drug and Therapeutics Bulletin. Withdrawing patients from antidepressants. Drug Therap Bull 1999; 37: 49–52. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry 1997; 154: 1760–62. Oehrberg S, Christiansen PE, Behnke K, et al. Paroxetine in the treatment of panic disorder: a randomised, double-blind, placebo-controlled study. Br J Psychiatry 1995; 167: 374–79. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clincial trial. Biol Psychiatry 1998; 44: 77–87. Haddad P, Anderson I. Antidepressants aren’t addictive: clinicians have depended on them for years. J Psychopharm 1999; 13: 291–92.

Control of meningococcal disease in west Africa Sir—Christopher Woods and colleagues (Jan 1, p 30)1 highlight the difficulty with developing an effective prevention strategy for meningococcal disease in west Africa. The current recommendation by WHO has been assessed with a Markov model and was found not to be cost effective.2 The two studies were based on mathematical models but came to different conclusions. Mathematical modelling is often an interesting academic exercise, but may bear no association to the biological model. Woods and colleagues made some assumptions in their mathematical model, which may have underestimated the potential benefit of routine vaccination. During the epidemic in Ghana, the time-toresponse for a mass vaccination campaign must have been substantially shortened by the fact that there was already a vaccination team working in the area on a yellow fever vaccination campaign. Setting up a team for such a mass vaccination campaign and procuring vaccines and consumables, at short notice, in a subSaharan country setting often pose a formidable threat to the fragile healthcare delivery systems in these countries. Also, official figures during meningococcal disease outbreaks are usually underestimates of the true magnitude of the epidemic: in part because a substantial number of cases of infection remain undetected or people die outside a health facility and sometimes for sociopolitical gains, there may be deliberate underreporting. Thus, routine vaccination with an adequate coverage before the onset of the mass vaccination campaign would have saved many more lives than projected by their model. The capacity to initiate and sustain disease surveillance is lacking in most sub-Saharan countries. The epidemic threshold set by WHO may be more appropriate for densely populated, large, urban communities. This threshold is difficult to apply in multiple settlements with populations of a few hundred, where as is often the case, health facilities are scarce and diagnostic facilities non-existent. The critical issue then, is the choice of vaccine for a routine immunisation programme. The meningococcal polysaccharide vaccine is not an appropriate choice. This vaccine does not impact carriage and has a short duration of protection, thus making it necessary to offer multiple doses of the

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vaccine. Multiple doses of this vaccine in infancy have been shown to attenuate response to the same vaccine, later in childhood.3 Several studies have proved the safety and immunogenicity of conjugate meningococcus A vaccines. If efficacy is established, it could be incorporated into the childhood immunisation programmes without necessarily increasing, significantly, the burden on already scarce resources in these countries. Extra clinic visits can be avoided by instituting a regimen that offers the vaccine alongside other antigens, or better still as a combination vaccine with other antigens such as diphtheria, tetanus, pertussis, Haemophilus influenzae type b antigens. The sub-optimal coverage of the current routine immunisation programmes in the sub-Saharan region should not be a deterrent to this development. The minimum coverage required to impact disease transmission by a vaccine that impacts carriage is not known and it may well be that with the advent of such a vaccine, a seemingly poor coverage may be just enough to impact transmission of this dreaded and deadly menace. More effort should be put into developing, more rapidly, conjugate vaccines, which are likely to impact carriage and thus have a significant herd effect. Steven Obaro MRC Laboratories, Fajara, PO Box 273 Banjul, The Gambia (e-mail: [email protected]) 1

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Woods CW, Armstrong G, Sackey S, et al. Emergency vaccination against epidemic meningitis in Ghana: implications for the control of meningococcal disease in West Africa. Lancet 2000; 355: 30–33. Bovier PA, Wyss K, Au HJ. A costeffectiveness analysis of vaccination strategies against N meningitidis menigitis in sub-Saharan African countries. Soc Sci Med 1999; 48: 1205–20. MacLennan J, Obaro S, Decks J, et al. Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood. Vaccine 1999; 17: 3086–93.

Authors’ reply Sir—The existing yellow fever teams did facilitate vaccine distribution once it was received, but our sensitivity analysis showed that even if the teams had not been previously established and an additional 2 weeks were needed to distribute vaccines, emergency mass vaccination would have prevented only 6–14% fewer cases. Steven Obaro comments that under reporting of cases may have

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affected our model; we acknowledged this to be likely and that it would affect the absolute number of cases prevented. However, the proportion of cases prevented by vaccination would remain unchanged. Obaro references a study by Boviet and colleagues, 1 in which they modelled a strategy of routine vaccination of school children aged 5 years, in whom the currently available meningococcal polysaccharide vaccine is likely to be effective, and concluded that the WHO outbreak response strategy would be less cost-effective than routine vaccination of children aged 5 years. While this strategy deserves further consideration, the authors presume that vaccination of children aged 5 years will have the same cost and coverage as the routine Expanded Program for Immunization (EPI); however, routine EPI does not target children aged 5 years and the additional visit required is not included in this model. In addition, vaccination of these children would not prevent disease among younger children nor does the model include any catch-up vaccination to provide protection to anyone older than 5 years before the start of the programme. Also, Bovier and colleagues did not take into account vaccine wastage which can range from 15% during mass vaccination campaigns to 40% during routine immunisation.2 Miller and colleagues2 used data from outbreaks to compare the current outbreak response programme with single dose at school entry as well as a 4-dose schedule vaccine programme, which could be implemented into the current EPI. In this study, the investigators concluded that given the relatively poor routine vaccination coverage in the region, the current strategy of outbreak identification combined with mass vaccination, although imperfect, would be more effective and less costly than routine use of the polysaccharide meningococcal vaccine. We agree with Obaro with regard to the limitations of meningococcal polysaccharide vaccine for routine childhood immunisation. A conjugate meningococcal serogroup A vaccine that provides long-lasting protection when given to infants is a better candidate for incorporation into routine childhood immunisation and an A/C meningococcal conjugate vaccine has already been shown to be safe and immunogenic in studies in Niamey, Niger. 3 Introduction of similar vaccines into routine immunisation programmes in Africa

appears to be the most effective way to prevent both sporadic disease and outbreaks. Christopher W Woods, Samuel O Sackey, Samuel Bugri, Bradley A Perkins, *Nancy E Rosenstein *National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA, and Ghana Ministry of Health, Accra, Ghana 1

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Bovier PA, Wyss K, Au HJ. A costeffectiveness analysis of vaccination strategies against N meningitidis meningitis in sub-Saharan African countries. Soc Sci Med 1999; 48: 1205–20. Miller MA, Wenger J, Rosenstein N, Perkins B. Evaluation of meningococcal meningitis vaccination strategies for the meningitis belt in Africa. Pediatr Infect 1999; 18: 1051–59. Campagne G, Garbar A, Fabre P, et al. Safety and immunogenicity of three doses of a N meningitidis A/C diphtheria conjugate vaccine in infants in Niger. Pediatr Infect Dis J 2000; 19: 144–50.

Sir—Christopher Woods and colleagues1 present a study of the reactive vaccination strategy recommended by WHO 2 for meningococcal meningitis epidemics in Africa (mass vaccination of the population when incidence reaches 15 cases per 100 000 inhabitants per week over 2 consecutive weeks or five cases per 100 000 inhabitants per week when an epidemic is already declared nearby). They conclude that, had 85% vaccine coverage been achieved within 1 week of crossing the epidemic threshold, 68% of meningitis cases could have been prevented. Reactive vaccination with the currently available polysaccharide vaccines is, for most countries in the meningitis belt, the only feasible approach.3 Nevertheless, the investigators’ predictions of programme effectiveness are optimistic. The investigators show that during the 1997 meningitis epidemic in Ghana, 5438 (23%) of cases were prevented, a figure which still fully justifies the vaccination campaign. They show that, after crossing the epidemic threshold, an increasing delay in the organisation of the campaign was associated with a striking decrease in the number of cases prevented, and field experience shows that it can take at least 2 to 3 weeks to decide, organise, and implement a vaccination campaign. Furthermore, current recommendations do not account for incomplete or delayed reporting of meningitis cases which reduce threshold sensitivity and cause further delay in epidemic detection. The success of the reactive vaccination strategy depends on the time available

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to mount a response and the rapidity of that response. The sooner the epidemic is detected, the better, so a sensitive epidemic indicator is needed. In one of the first studies of meningitis epidemic thresholds, carried out in Burkina Faso, 4 the investigators found that an incidence of ten cases per 100 000 inhabitants per week had a sensitivity of 100% and specificity of just under 60% for the detection of an epidemic, whereas a 2-week average of 15 cases per 100 000 inhabitants had a sensitivity of 72–93% and a specificity of 92–100%. This latter threshold was recommended for its better specificity and positive predictive value and was subsequently adopted by WHO.2 In two other studies5 the investigators found 100% sensitivity for a weekly meningitis incidence of ten cases per 100 000 inhabitants while specificity was 100% in Togo and 83% in Mali for district populations of about 20 000–100 000. With this lower threshold, on average more than a week was gained in both countries for implementation of epidemic control measures.5 In any imperfect test, there is a trade-off between sensitivity and specificity, but for meningitis epidemics, time is of the essence. A more sensitive threshold and an earlier alert will ultimately prevent more meningitis cases and deaths at no extra cost. As Woods and colleagues show, knowledge of meningitis incidence in neighbouring countries can help detect epidemics. Collaboration between countries and improvement of surveillance systems should be strongly encouraged. A lower threshold for declaring meningitis epidemics would allow a quicker response and should also be considered. *Rosamund Lewis, Francis Varaine, François Belanger, Nicolas Nathan, Lamine Diarra *Epicentre, 8 rue Saint Sabin, 75011 Paris, France, and Médecins Sans Frontières, Paris France; and Direction Nationale de la Santé Publique, BP 228 Bamako, Mali 1

2

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Woods CW, Armstrong G, Sackey SO, et al. Emergency vaccination against epidemic meningitis in Ghana: implications for the control of meningococcal disease in West Africa. Lancet 2000; 355: 30–33. WHO. Control of meningococcal disease— WHO practical guidelines. Geneva: WHO, 1995. Kaninda A-V, Varaine F, Henkens M, Pacquet C. Meningococcal vaccine in sub-Saharan Africa. Lancet 1997; 350: 1708. Moore PS, Plikaytis BD, Bolan GA, et al. Detection of meningitis epidemics in Africa: a population-based analysis. Int J Epidemiol 1992; 21: 155–62.

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Lewis RF, Diarra L, Belanger F, et al. Incidence thresholds for the detection of meningococcal meningitis epidemics in the African meningitis belt: Togo and Mali. Report of the fifth meeting of the international cooordinating group on vaccine provision for epidemic meningitis control (ICG), WHO, Geneva: Dec 9, 1999.

Heterogeneity of juvenile dermatomyositis Sir—We note the comments on childhood dermatomyositis made by Jeffrey Callen (Jan 1, p 53)1—ie, the impact of delay in diagnosis and the role of aggressive early treatment in prevention of calcinosis. The survey by Symmans and colleagues2 of consultant paediatricians in the UK and Ireland showed the median delay in diagnosis to be 4 months (range 0·3–31 months) for 48 cases of newly diagnosed juvenile dermatomyositis. Daily corticosteroid therapy was the first-line treatment option in 69% of cases. There were also other approaches to treatment—eg, 10% took the expectant approach (ie, no treatment at all—the disease will burn itself out). Despite apparent homogeneity of clinical presentation, juvenile dermatomyositis is a heterogeneous disease.3,4 The role of myositis-specific autoantibodies (MSA) and/or myositis associated autoantibodies (MAA) is controversial in its pathogenesis because most children with this disorder do not have a defined MSA or MAA, although many have antibodies to unidentifiable antigens.5 However, children with MSA or MAA have different clinical characteristics3,4 and the presence of some of these autoantibodies (eg, Jo1) is a recognised poor prognostic risk factor. Therefore, it appears logical that therapy in each patient should be more individualised. In particular, the secondline treatment options (methotrexate, cyclophosphamide, azathioprine, highdose intravenous immunoglobulin, cyclosporin, tacrolimus) should not be reserved only for steroid-refractory patients, but should be readily used in patients with unacceptable corticosteroid toxicity as well as in those with known risk factors for poor prognosis.3 The lack of good laboratory indicators of disease activity4 is another obstacle to optimum treatment, in particular the common error is controlling the abnormal creatine-kinase concentrations instead of the muscle weakness. Juvenile dermatomyositis is a rare disease with incidence of 1·9 per 1 million children aged under 16 years2 so that even specialist paediatricians from a

single centre will not see many children with this disorder in their working lives. Because of this, in the past few years we have changed our practice and instead of each of us seeking one or two patients per year, all the children with juvenile dermatomyositis referred to us are followed up in a combined clinic with input from paediatric immunology, rheumatology, and neurology. By gaining more experience, from our patients and from each other, we believe that we provide a good clinical service in line with the guidelines that the best practical indicator for evaluating response to the treatment and for subsequent follow-up of children with juvenile dermatomyositis is careful and expert clinical assessment.3,4 *Mario Abinun, Helen E Foster, Venkateswaran Ramesh, Alan W Craft Departments of *Paediatrics, and Rheumatology, The Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE4 6BE, UK (e-mail: [email protected]) 1 2

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Callen JP. Dermatomyositis. Lancet 2000; 355: 53–57. Symmons DP, Sills JA, Davis SM. The incidence of juvenile dermatomyositis: results from a nation-wide study. Br J Dermatol 1995; 34: 732–36. Rider LG, Miller FW. Classification and treatment of the juvenile idiopathic inflammatory myopathies. Rheum Clin North Am 1997; 23: 619–55. Pachman LM. Imperfect indications of disease activity in juvenile dermatomyositis. J Rheumatol 1995; 22: 193–97. Feldman BM, Reichlin M, Laxer RM, Targoff IN, Stein LD, Silverman ED. Clinical significance of specific autoantibodies in juvenile dermatomyositis. J Rheumatol 1996; 23: 1794–97.

Interpretation of Dutch BOA Trial Sir—We do not agree the main conclusion Bengt Lindblad comes to in his commentary1 on our study, The Dutch Bypass Oral anticoagulants or Aspirin study, published in the same issue. He states that antiplatelet agents are equally effective in prevention of graft occlusion after infrainguinal bypass surgery. He dismissed our pre-specified subgroup analysis by type of graft by saying that our patients were not stratified for this characteristic and, moreover, that subgroup analysis must be interpreted with caution, referencing the work of O’Neill.2 Although we acknowledge that in general caution should be used in intrepreting subgroup analyses,3 these need not to be disqualified if several conditions are met. Subgroup analysis should be specific before data analysis starts; there should be a patho-

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physiological background why any differences in treatment effect are anticipated or a replication of previous (subgroup) analysis is sought; and each subgroup should be of substantial size. Our subgroup analysis meets all three criteria: it was planned in the study protocol; our meta-analysis of aspirin and oral anticoagulants after infrainguinal bypass surgery suggested that aspirin was more effective in the prevention of occlusion of prosthetic grafts than that of venous grafts.4 Another meta-analysis confirms that the improvement of graft patency by antiplatelet drugs after peripheral bypass surgery can be attributed to an effect on patients with prosthetic grafts;5 and the subgroups were sufficiently large (1546 venous vs 1104 non-venous grafts) to allow a statistical interaction between graft material and treatment of p=0·002. As we explained in our discussion we refrained from stratification for graft material during randomisation because we wanted to allow preoperative randomisation at which stage the type of graft is not yet always known. A theoretical advantage of such stratification is a better balance of risk factors of graft occlusion between treatment groups within the graft type subgroups. However, imbalance is unlikely with large subgroups, moreover, when we took the minute differences between the treatment groups within the graft type strata into account our results were essentially similar. Hence, we believe there is no reason for concern about the interpretation of the graft type subgroup analysis with regard to the stratification issue. The work of O’Neill does not lend weight to such concerns because it addresses a completely different topic: the interpretation of secondary outcomes if there is no significance for the primary outcome.2 In conclusion, one of the main findings of our study is that the prevention of graft occlusion differs according to graft type: in venous grafts anticoagulation is better, in non-venous grafts aspirin is more effective. These differences may guide the decision on the treatment because no differences with regard to the composite secondary outcome of vascular death, myocardial infarction, stroke or amputation was found, either in the whole trial, or in the graft type subgroups. *A Algra, M J D Tangelder, J A Lawson, B C Eikelboom, on behalf of the Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study Group Julius Center for Patient Oriented Research, and Department of Vascular Surgery, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands (e-mail: [email protected])

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Lindblad B. Antithrombotic drug therapy after infrainguinal vascular surgery. Lancet 2000; 355: 334. O’Neill RT. Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance. Control Clin Trials 1997; 18: 550–56. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS2. Lancet 1988; 2: 349–60. Tangelder MJ, Lawson JA, Algra A, Eikelboom BC. Systematic review of randomized controlled trials of aspirin and oral anticoagulants in the prevention of graft occlusion and ischaemic events after infrainguinal bypass surgery. J Vasc Surg 1999; 30: 701–09. Watson HR, Skene AM, Belcher G. Graft material and results of platelet inhibitor trials in peripheral arterial reconstructions: reappraisal of results from a meta-analysis. Br J Clin Pharmacol 2000 (in press).

Nosocomial influenza infection Sir—The paper by William Carman and colleagues (Jan 8, p 93)1 and the accompanying commentary by Karl Nicholson2 highlight the importance of influenza transmission within longstay accommodation for elderly people. Our experience is that nosocomial influenza is also important in the acute hospital setting. Patient A was admitted to hospital on Dec 17, 1999, with postural hypotension. The following day patient B was admitted with anaemia. Because of a shortage of medical beds, both were transferred to the infectious diseases unit where they were placed in a four bedded side-ward. On Dec 24, 1999, patient C was admitted to a bed adjacent to those of patients A and B. Patient C had general malaise, fever, myalgia, and a mild deterioration of chronic obstructive pulmonary disease, and although not confirmed virologically, a clinical diagnosis of flu-like illness was made. Patients A and B started to have upper respiratory tract symptoms on Dec 26, 1999 and Dec 28, 1999, respectively. Both patients developed fever, general malaise, and bronchospasm. Nasopharyngeal aspirate samples taken from both patients on Dec 29, 1999 were positive for influenza A by direct immunofluorescence. These infections resulted in prolonged convalescence. Given the short incubation period of influenza A infection (1–4 days), we can be certain that patients A and B acquired influenza within the hospital. It seems likely that patient C was the source of infection. Transmission may also have occurred from a health-care

worker (5 of 29 nurses were off work with flu-like symptoms at this time) or a visiting relative (general practitioner consultation rate for flu-like illness in the area during week 53 of the year was 933 per 100 000).3 Carman and colleagues have shown, albeit with Nicholson’s reservations, that vaccination of health-care workers may reduce nosocomial influenza. This strategy would also reduce influenza and possibly days off work for health-care workers, although further studies are required.4 Rapid diagnosis of influenza is also important—virological analysis of nasopharyngeal aspirates can rapidly confirm influenza infection, but is an under-used diagnostic tool in UK medicine. During winter an increased use of nasopharyngeal aspiration would facilitate cohort-nursing of infected patients. However, pressure on beds means that it is unrealistic for patients with influenza to be isolated or accommodated together. Unvaccinated patients housed with influenza victims can be given amantadine or rimantadine to prevent influenza A infections. Their use has been limited, however, because of concerns about neurological sideeffects and viral resistance. Perhaps a better option is one of the new neuraminidase inhibitors, such as oseltamavir, which has been shown to prevent influenza in healthy adults.5 The best method of reducing nosocomial influenza, however, is to improve the uptake of community vaccination so that patients at high risk are protected before an admission to hospital. *Gavin Barlow, Dilip Nathwani Department of Infection and Immunodeficiency, Tayside University Hospitals NHS Trust, Kings Cross Hospital, Dundee DD3 8EA, UK 1

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Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000; 355: 93–97. Nicholson KG. Should staff in long-stay hospitals for elderly patients be vaccinated against influenza. Lancet 2000; 355: 83–84. Anon. Influenza and meningococcal infections. SCIEH Weekly Report 2000; 34: 13. Wilde JA, McMillan JA, Serwint J, Butta J, O’Riordan MA, Steinhoff MC. Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA 1999; 281: 908–13. Hayden FG, Atmar RL, Schilling M, et al, and the oseltamavir study group. Use of the selective neuraminidase inhibitor oseltamavir to prevent influenza. N Engl J Med 1999; 341: 1336–43.

Sir—William Carman and colleagues1 report on vaccination of health-care workers against influenza. Their

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paper, along with popular reporting of the current flu epidemic has left the impression that the strain on the UK National Health Service (NHS) would have been less if health-care workers had routinely been offered influenza vaccination.2 At the beginning of the winter of 1999–2000, Bury and Rochdale Health Authority, Manchester, UK, actively promoted the uptake of influenza vaccination among healthcare workers. We report the outcome of this initiative in two trusts that deal with acute health care. In both of these staff were offered vaccination free of charge via a letter signed by the Consultant in Communicable Disease Control. This letter also explained why vaccination was beneficial and where it was available. Posters and newsletters reinforced this message. A more intensive promotional campaign was undertaken in one of the trusts where a public health nurse was employed to raise awareness. In the course of visiting every work site, the nurse also attempted to allay anxiety and correct any misconceptions. These messages were also cascaded through the line management structure. The Occupational Health Department provided drop-in clinics and offered vaccinations at the work site. Staff vaccinated during October and November, 1999, were identified from records held by the occupational health departments; trust staff vaccinated in primary care were identified from reimbursement claims made by general practitioners. 454 (7·9%) of 5748 health-care workers were vaccinated during this period; 423 (93·2%) of 454 workers in occupational health departments and 31 (6·8%) of 454 workers in primary care. More intensive promotion had a minimal impact on uptake rates with a difference between the trusts of only 1·8% (95% CI 0·4–3·2). Although the number of vaccinations done within these occupational health departments in 1999 was three times greater than that recorded for 1998, uptake rates remained disappointingly low in both trusts and fell short of that likely to be required for herd immunity. 3,4 Vaccination of healthy adults has been shown to reduce the frequency of upper respiratory illness and the number of work days lost.5 Carmen and colleagues report that vaccination of health-care workers may lead to a reduction in mortality among patients. Our findings suggest that there is substantial resistance among NHS staff to influenza vaccination, even

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when offered free of charge. Bury and Rochdale Health Authority is currently investigating the reasons for this resistance. *Smita Halder, Leroy Benons, Paola Dey, Ciaran Woodman, Kevin Snee *Public Health Resource Centre, Centre for Cancer Epidemiology, University of Manchester, Manchester M20 4QL, UK; and Department of Public Health, Bury and Rochdale Health Authority, Manchester 1

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Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of health care workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 2000; 335: 93–97. Department of Health. CMO’s Update 23—a communication to all doctors from the Chief Medical Officer. August 1999: 6. Warburton MF, Jacobs DS, Langsford WA, et al. Herd immunity following subunit influenza vaccine administration. Med J Aust 1972; 2: 67–70. Patriarca PA, Weber JA, Parker RA, Orenstein WA, Hall WN, et al. Risk factors for outbreaks of influenza in nursing homes: a case control study. Am J Epidemiol 1986; 124: 114–19. Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995; 333: 889–93.

Is Japan losing the fight against tobacco? Sir—Tobacco is the largest preventable cause of mortality and morbidity in industrialised countries. Also, tobacco-attributed disease is probably the leading projected global burden, particularly in developing countries.1 As a consequence, WHO has promoted the Tobacco Free Initiative as one of its major activities. Despite the secular trend of decreasing tobacco consumption in most industrialised countries, smoking prevalence in Japan continues to be high.2 Because of a possible surge of tobacco-associated mortality and morbidity in the near future, the goal of halving smoking prevalence and tobacco consumption by 2010 was set on Aug 12, 1999, by the committee of the Japan Ministry of Health and Welfare in its innovative draft proposal for the health policy in the 21st century. The committee also proposed rigorous anti-smoking measures, such as increasing tobacco tax and banning commercial advertising. During the final review of the proposal, however, the goal set by the public health practitioners and health officials was rejected on Feb 29, 2000, and only fairly ineffective anti-smoking measures were accepted. Lobbyists in the leading Liberal Democratic Party, whose major focus is loss in sales, production work force, and tax

revenues, claimed that the health effect of smoking is still controversial and the government should not set a specific goal for individual preferences. It is clear that the political lobbies swayed the final decision and that the concern about economic loss outweighed the future health gains. However, losses incurred by the tobacco industry and farmers can be minimised in the long-run. Tax revenues can be increased even with decrease in sales since price-elasticity of tobacco is below unity.3 Healthier life without disability, for which the proposal was originally drafted, would alter the lifetime health-care costs and welfare payments in a non-smoking population. Probably few, if any, would agree that smokers should just smoke while they work and die prematurely, leaving the welfare budget untouched. Health itself is intrinsically valuable and cannot be compared with material welfare.4 The government should pay attention to current and future diseases associated with tobacco rather than to the importance of the tobacco market. So are we losing the fight against tobacco in Japan? Unfortunately, yes, for now. However, the efforts by public-health practitioners and medical personnel to promote antismoking measures should not be discouraged and the fight against the largest threat to public-health should be continued. *Kenji Shibuya, Hideki Hashimoto Department of Hygiene and Public Health, Teikyo University School of Medicine, Kaga, Itabashi, Tokyo, Japan (e-mail: [email protected]) 1

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Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study. Lancet 1997; 349: 1498–504. Ministry on Health and Welfare. Annual report of health and welfare, 1997–98. Tokyo: Ministry of Health and Welfare, 1998. Townsend J, Roderick P, Cooper J. Cigarette smoking by socioeconomic group, sex, and age: effects of price, income and health publicity. BMJ 1994; 309: 923–27. Anand S. Population, well-being, and freedom. In: Sen G, Germain A, Chen L, eds. Population policies reconsidered. Health, empowerment, and rights. Cambridge: Harvard University Press, 1994: 75–85.

Sir—Many countries battle against growing expenditure on health. Japan is no exception, especially because it faces the deepest recession since the war. US$242 billion was spent on health care in Japan in 1997, equivalent to 7·5% of gross domestic product. The annual death toll attributable to smoking is estimated to amount to 95 000 in Japan, and the cost for tobacco-associated ill health

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Homicide, novel antipsychotics, and non-compliance

exceeds $10·9 billion. It is therefore welcome for the government to propose the project Healthy Japan for the 21st century. In draft, it included a plan that the rate of smokers would be reduced to the half of the current level (male 53%; female 13%) by the year of 2010. Sadly, the goverment has, however, withdrawn this initially-set target after hearing claims from Japan Tobacco Industry, a major tax payer, and politicians representing tobacco growers. Lack of policies on tobacco regulations is, however, visible in Japan. A recent attempt to increase tax in cigarettes also failed: a packet of cigarettes costs only ¥250 (£1·40). There are still many vending machines in the streets that are readily accessible to teenagers. The price of one piece of nicorette (chewing gum containing nicotine) is ¥156 (£0·87) in Japan and £0·15 (¥27) in UK and, furthermore, a prescription is required. Needless to say, the administrative role is to improve the health of the nation’s people and to seek preventative means. To achieve this, a strong stance sometimes must be made. Nobody could argue against decisions made on the basis of scientific evidence. Conservativeness ought not to be erroneously considered to be prudent. To my surprise, sildenafil (Viagra), a medication for erectile dysfunction, was introduced in Japan immediately after approval by the US Food and Drugs Administration. 3 months later (June 1999), the contraceptive pill, approval of which had long been on the shelf, was at last approved by the Japan’s Department of Health. Also, nearly 7 years have passed since I wrote my paper “Why is clozapine not available in Japan?”.1 Clozapine, an atypical antipsychotic agent whose efficacy has been firmly established especially for people with refractory schizophrenia—a devastating condition—and has been used worldwide (66 countries as of 1999), is still not available in Japan. Health policy planners need to recognise that they are in a powerful position to save many precious lives and preclude adverse consequences as a result of ill health.

Sir—A man in his late twenties was admitted to a medium secure unit under sections 48/49 of the UK Mental Health Act 1983, charged with the murder of a close relative. His mental illness included symptoms of mainly persecutory delusional beliefs, delusional perception, and auditory hallucinations. He was prescribed risperidone as first-line treatment while living in the community, but he complained of drowsiness and he told his clinician that he had defaulted from the treatment. He was admitted to hospital and was treated with the conventional oral antipsychotic, sulpiride 200 mg twice daily. He failed to show an adequate response after 3 months and he was given a repeat trial of risperidone. He made good progress on risperidone 1 mg twice a day, although his symptoms did not fully resolve. During periods of leave, his principal carer did not believe that he was compliant with treatment. He was discharged on risperidone 2 mg a day but he required a further admission to hospital when risperidone was increased to 3 mg a day. He was discharged while he still had delusional beliefs. After his discharge he stopped his medication in order, he said, to remain alert to potential danger and carried a knife for selfdefence. The tragic outcome was that he killed a member of his immediate family. Psychiatric examinations after his arrest showed that he was at high risk of suicide as a result of remorse over his actions. There is a widespread belief that new antipsychotics, because of their lesser extrapyramidal side effects, may be more acceptable to patients than the older neuroleptics, and may therefore improve patient compliance. 1,2 There is as yet no systematic evidence that this benefit

I thank the Theodore and Vada Stanley Foundation for financial support.

Noriyoshi Takei Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan (e-mail: [email protected]) 1

Nanko S, Takei N. Why is clozapine not available in Japan? Lancet 1993; 341: 490.

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holds true, and the newer antipsychotics have other side effects that may be just as off-putting.3 We have seen three individuals with schizophrenia charged with homicide while prescribed novel antipsychotics (table); all presented in London, UK, between November, 1998, and April, 1999. Trials have shown that if a group of patients are randomly assigned novel or older oral antipsychotics, the dropout rate is lower for the novel antipsychotic group.4 This is not the same as showing that those with an established history of non-compliance will be more inclined to comply with newer drugs. The patients in this report would have been offered depot neuroleptics. Reviews of factors associated with homicides by the mentally ill in contact with services have not emphasised the importance of noncompliance with medication. Although homicide in association with non-compliance with oral novel antipyschotics is rare, the association may point towards a much greater risk of non-fatal violence.5 It is premature to dispense with the use of depot neuroleptics in patients with a history of non-compliance or a risk of violence when psychotic. S W Mikhail, *H G Kennedy Camlet Lodge Regional Secure Unit, Chase Farm Hospital, The Ridgeway, Enfield, EN2 8JL, UK (e-mail: [email protected]) 1

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Kasper S. How much do novel antipsychotics benefit the patients. Int Clin Psychopharmacol 1998; 13 (suppl 3): S71–77. Gaebel W. Towards the improvement of compliance: the significance of psychoeducation and new antipsychotic drugs. Int Clin Psychopharmacol 1997; 12 (suppl 1): S37–42. Barnes TRE, McPhillips MA. Critical analysis and comparison of the side-effect and safety profiles of the new antipsychotics. Br J Psychiatry 1999; 174 (suppl 38): 34–43. Tran PV, Dellva MA, Tollefson GD, Beasley CM, Potvin JH, Kiesler GM. Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the

Time since onset of illness

Time since discharge to community

Past evidence of noncompliance

Past evidence of violence to self or others

Psychotic at time of discharge

Medication

NonPsychotic compliance at time of at time of homicide homicide

Case 1

1 year 8 months

4 months

Yes

Yes

Yes

Risperidone 3 mg/day

Yes

Yes

Case 2

2 years

6 months

Yes

Yes

Yes

Olanzapine 20 mg/day Thioridazine 50 mg/day

Yes

Yes

Case 3

5 years

13 days

Yes

No

Yes

Olanzapine 20 mg/day

Yes

Yes

Three patients with schizophrenia charged with homicide while prescribed novel antipsychotics

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5

acute treatment of schizophrenia. J Clin Psychiatry 1997; 58: 205–11. Kennedy HG, Iveson RY, Hill O. Violence, homicide and suicide: strong correlation and wide variation across districts. Br J Psychiatry 1999; 175: 462–66.

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Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: 407–13. Womack M, Kemmerer KS, Rose WC. The relation of methionine and cystine to growth. J Biol Chem 1937; 121: 403–11. Mann GV, Andrus SB, McNally A, Stare FJ. Experimental atherosclerosis in Cebus monkeys. J Exp Med 1953; 98: 195–218.

The homocysteine question Sir—Nicholas Dudman (Dec 11, p 2072)1 provides an alternative view of homocysteine, however there is another explanation for the role of homocysteine in vascular disease. Two diseases have been attributed to raised concentations of homocysteine. Homocysteinuria has one form responsive to pyridoxine and another that is not; the second form is effectively treated with dietary restriction of methionine and supplementation with cystine. Both these disorders are caused by genetic impairment of cystathionine synthase and show that dietary methionine is ineffectively converted to cystine.2 The second disorder is coronary heart disease. Raised concentrations of homocysteine are estimated to be associated with 10–15% of instances of coronary heart disease.3 While it is widely assumed that raised blood concentrations of homocysteine are the cause of disease in both disorders, there is little substantial evidence to support this explanation. A more plausible explanation for both disorders is a deficiency of cystine caused by interruption of the methionine-to-cystine transformation. Cystine is an important constituent of many proteins and methionine is a major source of cystine. The essentiality of cystine is conditioned by the transformation of methionine to cystine.5 Raised concentrations of homocysteine may be a consequence, not a cause of these disorders. In 1953, my co-workers and I5 showed that a dietary deficiency of methionine and cystine led to atherosclerosis in primates. If cystine deficiency is the causal mechanism of disease in homocysteinuria and in some instances of coronary heart disease, then the proper remedy is supplementation with dietary cystine. A treatment trial is needed to evaluate this proposal. George V Mann 324 Cardwell Road, McMinnville, TN 37110, USA 1 2

Dudman NPB. An alternative view of homocysteine. Lancet 1999; 354: 2072–74. Peterschmitt MJ, Simmons BS, Levy HL. Reduction of false negative results in screening of newborns for homocystinuria. N Engl J Med 1999; 341: 1572–76.

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Social dis-ease of collective irresponsibility Sir—The categories and structure of hospital medicine have fragmented and distorted our comprehension of what it is to suffer and to heal. The unquestioned power and influence of this new form of social organisation has only recently begun to come under sustained scrutiny. But contrary medical voices seem like those of dissidents or heretics, rather than welcome additions to a liberating debate, and I can personally testify to the way this leads to marginalisation and even frank suppression. In 1975 I was seconded to work in WHO’s smallpox eradication programme in Bangladesh. During the time that I was there I became increasingly concerned about the ethical justification of the programme. The overriding concerns of the WHO personnel seemed to be: to save developed countries from the expense of having to vaccinate their own populations; and to ensure the longterm future of their own posts within WHO, which were seen to be under threat if the programme were to fail. This led them to conclude that almost any means of eradication could be justified. At the same time they were able to give public justification for their actions by invoking a crude utilitaritian argument. This was to claim that the suffering of people and social detriment, which was the inevitable accompaniment of the programme they adopted, would be outweighed by the long-term good of global smallpox eradication. This was then seen as an unchallengeable argument, which led to a battlefield mentality, where those working in the field were expected to express jingoistic fervour, or risk being seen as conscientious objectors. Worse still, it generated a colonial attitude, in which any failure to co-operate, by the Bangladeshi government or people was interpreted as a result of ignorance or intransigence. Political pressure was exerted on the government to accept that at certain times a small number of WHO expatriates would take charge of half the total health-service personnel in the whole country, with little regard to

the general consequence for health care. In individual cases it also involved a combination of large monetary inducements for the reporting of suspected cases, which proved socially divisive. Severe punitive measures, such as relocation to other areas away from their families, were served on lowranking and poor health-service staff who failed to carry out their allocated duties. All this must be set against the background of the country (then East Pakistan) having previously eradicated smallpox without outside assistance, before the war between India and Pakistan which led to its re-emergence. I resigned from the programme after a month and returned to Britain, where I was cross-questioned as to why I had left what my superiors took to be a selfevidently worthy endeavour. While it was acknowledged that there might have been ethical reasons for resigning, these were construed in terms of narrowly defined technical sisues, such as the administration of faulty or inappropriate vaccines. My own more wide-ranging and general assessment was therefore regarded as invalid, and was condescendingly dismissed as evidence of my incompetence to make a reasonable judgment, either because of my immaturity, or ignorance of the wider situation. The primeval fear engendered by smallpox is only a heightened example of a more general fear, arising from a social dis-ease which is endemic in our society. It follows our inability to come to terms with how to live our lives and cope with our deaths when hypnotised by the seductive prospect of an everincreasing superabundance of material wealth. It makes it almost impossible for us to focus on any large and rounded truths, even though many yearn for and are dimly aware of the pressing need to do so. This then is the route which blinds us to our collective irresponsibility. David Greaves University of Wales, Swansea School of Health Science, Centre for Philosophy and Health Care, Singleton Park, Swansea SA2 8PP, UK 1

Evans M, Greaves D. Exploring the medical humanities. BMJ 1999; 319: 1216.

DEPARTMENT OF ERROR Benefits of irradiation for DCIS: a Pyrrhic victory—In this Commentary by M J Silverstein and M D Lagios (Feb 12, p 510), the affiliation for M J Silverstein should be, “Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA”. Clozapine and sudden death—In this Correspondence letter by Ingo Suttmann and colleagues (March 4, p 842), the second author’s name is Sebastian Dittert.

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