Statins for prevention of stroke

CORRESPONDENCE

carotid—the patients for whom surgery is recommended. The difference in favour of surgical treatment is much greater for non-disabling than for disabling stroke, and no overall advantage is seen for the combined endpoint of disabling stroke or death. These crude calculations do not give the full picture, which could be better provided by an analysis of survival free of disabling stroke, similar to that shown in figure 4 of the report.1 This anaysis would not only be less open to observer bias but would also be more useful for individual clinicians and patients and provide better information on cost-effectiveness for commissioners of health services. Even if such analysis indicates clear benefits for surgery in patients with tight stenosis, doubts will remain about its application in routine practice, where neither the rigour of case selection3 nor the complication rates of carotid endarterectomy4 match up to the standards of the large clinical trials. Improvements in medical approaches to secondary prevention5 will further erode any advantage for surgery, making the balance of risks and benefits too close to call. David Barer Department of Medicine, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK 1

2

3

4

5

European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998; 351: 1379–87. Ottenbacher KJ, Jannell S. The results of clinical trials in stroke rehabilitation research. Arch Neurol 1993; 50: 37–44. Cebul RD, Snow RJ, Pine R, Hertzer NR, Norris DG. Indications, outcomes and provider volumes for carotid endarterectomy. JAMA 1998; 279: 1282–87. Wennberg DE, Lucas FL, Birkmeyer JD, Brendenberg CE, Fisher ES. Variation in carotid endarterectomy mortality in the Medicare population. JAMA 1998; 279: 1278–81. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13.

Sir—The European Carotid Surgery Trial (ECST)1 offers an unprecedented opportunity to study the long-term prognosis of transient ischaemic attacks (TIAs) in a large cohort of patients randomised to surgery or medical treatment. Previous studies showed a better prognosis for retinal TIAs than for hemispheric TIAs: medically treated patients with high-grade carotid stenosis who presented with a retinal

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TIA had an estimated 2-year risk of ipsilateral stroke of 16·6%, compared with a 43·5% risk of ipsilateral stroke in patients with a hemispheric TIA.2 This difference was highly significant and the strokes in the group with retinal TIAs tended to be less severe. Whether patients with retinal TIAs should be managed differently from patients with hemispheric TIAs is not clear. A subgroup analysis from ECST would help to clarify this question, and we look forward to a publication of the relevant data. *Anna Fierz, Eric Eggenberger Center for Clinical Neurosciences and Ophthalmology, A-217 Clinical Center, East Lansing, MI 48824, USA 1

2

European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998; 351: 1379–87. Streifler JY, Eliasziw M, Benavente OR, et al. The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. Arch Neurol 1995; 52: 246–49.

aged patients with coronary heart disease. This group of patients is only a small subset of the population susceptible to stroke, and among this subset a large proportion of the strokes are caused by ischaemia, mostly due to atherosclerotic disease. The effect of statin treatment is therefore likely to be beneficial. However, since the pathogenesis of stroke is thought to be heterogeneous, there is no evidence that all types of stroke and thus various groups of patients will benefit from treatment. In our meta-analysis of the available data4 we showed that statins do not reduce the number of fatal strokes. Thus, with the data available it is difficult to extrapolate the beneficial effects of statins in middle-aged individuals to the elderly population among whom strokes occur most frequently. Extrapolation becomes even more hazardous when realising that among the elderly cholesterol is not a risk factor for coronary heart disease.5 *Gerard J Blauw, A Margot Lagaay, Rudi G J Westendorp

Statins for prevention of stroke Sir—We support Clive Rosendorff’s conclusion in his April 4 commentary1 that statins may be effective in the prevention of stroke, but we disagree with his underlying assumptions and clinical reasoning. In sharp contrast with his opening statement, there is conclusive evidence that cholesterol is not a risk factor for stroke.2 The fact that non-statin cholesterol-lowering drugs lack beneficial effects on risk of stroke corroborate this finding. In this respect, the finding that statins reduce the risk of stroke are amazing. A possible explanation is that statins have a cholesterol-independent effect on cerebrovascular disease. The effects of statins on coronary heart disease support this hypothesis. The risk reduction of coronary events by statins is largely independent of the cholesterol concentration at baseline.3 The clinical message of these observations is that cholesterol concentrations should not be used to consider treatment for the prevention of stroke. Should all individuals at high risk of coronary and cerebrovascular disease be offered intensive lipid-lowering treatment with statins to prevent stroke? The real answer is that we do not know yet. The reported favourable effects of statins on reducing the risk of stroke are obtained from middle-

Section of Gerontology and Geriatrics, Department of General Internal Medicine and Clinical Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300RC, Leiden, Netherlands 1 2

3

4

5

Rosendorff C. Statins for the prevention of stroke. Lancet 1998; 351: 1002–03. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Lancet 1995; 346: 1647–52. Scandinavian Simvastatin Survival Study Group. Baseline cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995; 345: 1274–75. Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, statins and cholesterol. A meta-analysis of randomised, placebo-controlled, double-blind trials with HMG-CofA reductase inhibitors. Stroke 1997; 28: 946–50. Weverling-Rijnsburger AWE, Blauw GJ, Lagaay A, Knook DL, Meinders AE, Westendorp RGJ. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350: 1119–23.

Sir—Clive Rosendorff’s commentary1 highlights a paradox: why should lowering cholesterol with statins lead to a reduction in stroke morbidity and mortality that is not evident with other cholesterol-lowering regimens? Cholesterol concentrations are not directly correlated with stroke.2 One admittedly speculative explanation not discussed is that treatment with statins results in lower blood pressure, through a mechanism that has already been proposed.3 Raised blood pressure is the single most important risk factor

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for stroke and an important risk factor for coronary artery disease. With respect to stroke, benefits of lowering blood pressure are seen within 2–3 years. Patients with established cardiovascular disease have rarely been enrolled in trials of antihypertensives, even though they are likely to gain greatest benefit from blood pressure lowering, because of their higher absolute risk of cardiovascular mortality: but they are precisely the patients enrolled in the statin secondary prevention trials. Another statin paradox—why benefit from treatment with statins seems to extend to people aged 65–75 when cohort studies 4 (including Framingham5) strongly suggest that cardiovascular mortality is not related to cholesterol concentration at these ages—would also be explained if blood pressure were reduced by statins. Unfortunately, changes in blood pressure were not reported in the three largest studies of statins (4S, WOSCOPS, and CARE), although baseline concentrations were given. Any lowering of blood pressure would have partly contributed to the reduction of mortality and weakened the effect of cholesterol lowering, but this effect should not be a reason for omitting results. If statins reduce blood pressure as well as alter lipid profiles, then they could be seen as tackling two of the major risk factors for cardiovascular disease in a single agent. Although any change may have been non-significant, results with respect to blood pressure should have been reported. Notwithstanding this speculation or the evidence summarised by Rosendorff, the issues of prioritisation of treatment and cost will still have to be addressed, at least in the UK. R E Fey Public Health Medicine, Gloucester Health Authority, The Docks, Gloucester GL1 2EL, UK 1 2

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4

5

Rosendorff C. Statins for prevention of stroke. Lancet 1998; 351: 1002–03. Marmot MJ, Poulter NR. Primary prevention of stroke. Lancet 1992; 344: 344–47. Goode GK, Miller JP, Heagerty AM. Hyperlipidaemia, hypertension, and coronary heart disease. Lancet 1995; 345: 362–64. Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholestero and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA 1994; 272: 1335–40. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham Study. JAMA 1987; 257: 2176–80.

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Community-acquired meticillin-resistant Staphylococcus aureus in Australia Sir—Meticillin-resistant Staphylococcus aureus (MRSA) is common in hospitals worldwide, but is not an infection we expect to be community acquired. Since January, 1997, we have seen many infections with communityacquired MRSA in patients who have had no previous association with hospitals or nursing homes (table). Community-acquired MRSA has been detected previously in Australia but initially only in remote areas;1,2 these strains are now found in nearly all capital cities. We believe these are not hospital isolates that have gone into the community, since most have sensitivity patterns distinct from hospital isolates. Most isolates remain sensitive to erythromycin, tetracycline, trimethoprim, ciprofloxacin, and gentamicin. We did confirmatory tests for meticillin resistance with the mecA gene which was detected in all 20 isolates tested. Phage typing was done on 32 isolates from two Sydney hospitals. Seven isolates were not typable and 25 isolates showed 13 distinct phage-typing patterns, none of which have been seen in Sydney hospital MRSA isolates. Patients have presented with bacteraemia but more frequently with infections of the skin and soft tissues. We found a disproportionate number of cases in people from the South Pacific (eg, Tonga, Western Samoa). Riley and colleagues3 reported that in Auckland, community-acquired MRSA is common among Polynesians—it has a high prevalence of up to 10% of all community-acquired S aureus isolates, and predominantly belongs to the Western-Samoan phage group. Many strains circulating in Australia were City*

Number Main types of infection of (number of cases) isolates

Brisbane

12

Canberra

4

Melbourne

6

Sydney 19 (hospital 1) Sydney 25 (hospital 2) Sydney 8 (hospital 3)

Soft tissue (4), abscess (6), skin (1), blood (1) Soft tissue (1), skin (1), bone (1), blood (1) Soft tissue (4), skin (1), genital (1) Skin (13), genital (2), blood (1), eye (2), respiratory (1) Skin (12), abscess (7), respiratory (5), blood (1) Abscess (5), skin (2), blood (1)

None of the patients had previous contact with a hospital or nursing home. *Darwin and Perth also have frequent isolates of community-acquired MRSA.1,2

Isolates of MRSA detected from community patients since January, 1997

probably derived from clones that originated in the South Pacific. Cases of community-acquired MRSA have been reported among children in Chicago.4 In Australia and New Zealand, these strains are well established and widespread; we can only expect that their numbers will increase. This community-acquired MRSA presents major difficulties for the empiric treatment of communityacquired life-threatening staphylococcal infections. Current standard therapy is to use a penicillinase stable ␤-lactam parenterally (eg, flucloxacillin or cephalothin), to which communityacquired MRSA is resistant. There are, however, no suitable alternative drugs that are predictably active, easy to administer, safe, and inexpensive, or not themselves associated with concerns of rapidly developing resistance if used widely, especially as single agents. Possibilities include the addition of gentamicin, ciprofloxacin, or fusidic acid in the empiric therapy with a ␤-lactam while awaiting sensitivity and culture results. Although vancomycin is the best agent to treat serious infections, once MRSA is confirmed on testing, we believe that the widespread use of vancomycin will hasten the emergence of resistance. We therefore do not recommend its empiric use unless the prevalence of community-acquired MRSA exceeds an acceptable threshold. Cultures should be obtained for susceptibility testing even in less serious disease since we can no longer presume that community-acquired S aureus infections will respond to ␤lactams. We believe community-acquired MRSA is likely to be under-recognised because meticillin resistance can be difficult to detect in the laboratory. *Peter Collignon, Iain Gosbell, Alison Vickery, Graeme Nimmo, Tas Stylianopoulos, Tom Gottlieb, on behalf of the Australian Group on Antimicrobial Resistance (AGAR) *Departments of Microbiology and Infectious Diseases, Canberra Hospital, Garran, ACT 2606, Australia; Department of Microbiology and Infectious Diseases, South Western Area Pathology Service, Liverpool, New South Wales; Microbiology Department, Royal Prince Alfred Hospital, Camperdown, New South Wales; Microbiology Department, Princess Alexandra Hospital, Brisbane, Queensland; Microbiology Department, Royal Childrens Hospital, Melbourne, Victoria; and Concord Repatriation General Hospital, Concord, New South Wales 1

2

Riley TV, Pearman JW, Rouse IL. Changing epidemiology of methicillin-resistant Staphylococcus aureus in Western Australia. Med J Aust 1995; 163: 412–14. Maguire GP, Arthur AD, Boustead PJ, Dwyer B, Currie BJ. Emerging epidemic of community-acquired methicillin-resistant

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