Letters to the Editor

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1 Age and Ageing 1999; 28: Letters to the Editor 1999, British Geriatrics Society Drug-induced agranulocytosis in older people. A case series of 25 patients SIR We retrospectively analysed 25 consecutive cases of drug-induced agranulocytosis in older patients in the departments of geriatrics, internal medicine, oncohaematology and rheumatology of the Hôpitaux Universitaires de Strasbourg (a tertiary referral centre), between 1985 and Patients had to be 70 or older and have unquestionable drug-induced agranulocytosis. All data were obtained from the patients files, including medical history, clinical status on referral, relevant bacteriological and biochemical data, blood count and marrow examination (when available). Treatment modalities, use of haematopoietic growth factors, length of time for the neutrophil count to reach > /l and outcome were also recorded. The median age was 79 years (range 70 95). The sex-ratio was 1.47, with a predominance of women. A single drug was implicated in 23 cases, whereas the causative agent was unclear in two cases (Table 1). Twenty-two patients ingested multiple drugs (median 3). A previously normal blood count was not established for all patients before diagnosis, so it is possible that other factors (such as infection) may have caused the agranulocytosis. Diagnosis was made fortuitously in six patients and 19 presented with various symptoms, septicaemia and septic shock being the most frequent. Six patients received haematopoietic growth factors for a mean of 7 days, but their recovery period did not differ from the other patients. The outcome was generally favourable, although two patients, (aged 81 and 90) died of septic shock. A pathogen was found in 10/25 patients, with Staphylococcus epidermidis in three, Escherichia coli (in two) and Staphylococcus aureus, Micrococcus, Pseudomonas aeruginosa, Moraxella and Streptococcus D in one each. The annual incidence of drug-induced agranulocytosis varies between 2.4 and 15.4 cases/year/10 6 in the USA and is 4.7 cases/year/10 6 in Europe [1, 2]. Older people are over-represented in all published series, but there is no study on this subset of patients. Drug intake is obviously more frequent in older people, with increased risk of toxicity. Moreover, self-medication is common, especially with anti-inflammatory drugs, and age-related memory and attention deficits also make both instruction and supervision by physicians difficult. Six patients were asymptomatic at diagnosis. These data are consistent with other reports [3]. Septicaemia and septic shock were found in 24% of cases. A bacterial pathogen was found in 40% of cases, which is more frequent than in other series [2, 4]. Antibacterial agents were the agents mainly involved in our series (39%). Although the use of sulphamethoxazole/trimethoprim is discouraged in the UK, it is commonly used in France, despite the fact that physicians are frequently informed of the drug s toxicity. Our 8% mortality rate is also consistent with other reports: from 3% [3, 5] to 10 20% in other series [4, 6, 7], regardless of age. Several prognostic factors for druginduced agranulocytosis have been identified; these include age, absolute neutrophil count, percentage of myeloid precursors in bone marrow, presence of septic shock, bacteriaemia and renal insufficiency [4, 7, 8]. Drug-induced agranulocytosis remains a severe adverse event in older people. Broad-spectrum antibiotics are warranted. The place of haematopoietic growth factors remains to be defined. JEAN-EMMANUEL KURTZ 1,EMMANUEL ANDRES 2, FRÉDÉRIC MALOISEL 1,VALÉRIE KURTZ-ILLIG 3,DAMIEN HEITZ 4, JEAN SIBILIA 5,MARC IMLER 2,PATRICK DUFOUR 1 Departments of Onco-Hematology 1, Internal Medicine 2, Geriatrics 4 and Rheumatology 5,Hôpitaux Universitaires de Strasbourg, Strasbourg, France Department of Geriatrics 3, CHG Ste Catherine, Saverne, France Fax: (+33) jean-emmanuel.kurtz@chru-strasbourg.fr Table 1. Drugs causing agranulocytosis Drug class Drug (and no. of cases)... Anti-inflammatory drugs Phenylbutazone (1), dapsone (1) Anti-aggregating drugs Ticlopidine (2), acetylsalicylic acid (1) Antibacterial agents Sulphamethoxazole trimethoprim (3), cefotaxime (1), vancomycin (1), piperacillin (1), imipenem (1), amoxycillin (2) Antidepressants Mianserin (1), Minaprine (1) Indalpin (2) Antithyroid agents Benzylthiouracil (1), carbimazole (2) Cardiovascular agents Captopril (1), Fluindione (1) Drug not established Two patients 1. Strom BL, Carson JL, Schinnar R, Snyder ES, Shaw M. Descriptive epidemiology of agranulocytosis. Arch Intern Med 1992; 152: Kaufman DW, Kelly JP, Levy M, Shapiro S. The drug etiology of agranulocytosis: an update of the International Agranulocytosis and Aplastic Anemia study. Pharmacoepidemiol Drug Safety 1993; 2: Vial T, Pofilet C, Pham E, Payen C, Evreux JC. Agranulocytoses aiguës médicamenteuses: experience du centre régional de pharmacovigilance de Lyon sur 7 ans. Thérapie 1996; 51: Paitel JF, Stockemer V, Dorvaux V, Witz F, Guerci A, Lederlin P. Agranulocytoses aiguës médicamenteuses. Etude clinique à propos de 325

2 30 patients et évolution des étiologies sur 2 décennies. Rev Med Intern 1995; 16: Sprikkelman A, De Wolf JTM, Vellaga E. The application of hematopoietic growth factors in drug-induced agranulocytosis: a review of 70 cases. Leukemia 1994; 8: Arneborn P, Palmblad J. Drug induced neutropenia: a survey for Stockholm Acta Med Scand 1982; 212: Julia A, Olono M, Bueno J et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Hematol 1991; 79: Lipsker D, Maloisel F, Grunenberger F et al. Neutropénies et agranulocytoses médicamenteuses: expérience du CHU de Strasbourg J Med Strasbourg 1992; 23: Do we overlook respiratory symptoms and airflow obstruction in elderly medical admissions? SIR Airflow obstruction is often overlooked in elderly subjects living at home [1]. Whether this is also true of acute elderly admissions is not known. We prospectively studied 100 consecutive patients aged 65 years and above admitted to acute general medical wards at a district general hospital. We excluded patients who were known to have chronic obstructive airways disease and those unable to perform spirometry. Within 5 days of admission, we asked subjects to complete a respiratory questionnaire previously used in epidemiological studies of respiratory disease in older people [2]. We performed spirometry on all patients. If airflow obstruction was present [the ratio of forced expiratory volume in 1 s (FEV 1 ) to forced vital capacity (FVC) was <60% and the FEV 1 <80% predicted], we repeated measurements after 200 mg salbutamol inhaled via a large volume spacer device. Reversibility was taken to be >15% improvement in FEV 1 with a 200 ml increase in FEV 1 [3]. If patients had no reversibility to salbutamol, we repeated spirometry after 40 mg ipratropium bromide. Of 100 patients, 54 were excluded (22 had known chronic obstructive airways disease, 32 were unable to perform spirometry). Of 46 patients not known to have chronic airflow obstruction (mean age 80 years, range 65 93), 35 (76%) reported any respiratory symptom. Twelve (26%) patients had airflow obstruction, of whom five (42%) demonstrated reversibility to bronchodilators. At least one respiratory symptom was reported by all 12 patients with undiagnosed airflow obstruction and by 23 of 34 (68%) patients without airflow obstruction. Respiratory symptoms and airflow obstruction in older people admitted to hospital are common and frequently overlooked. Respiratory symptoms have low specificity for respiratory disease in older people [4]. Studies are currently underway to address whether patients with undiagnosed chronic airflow obstruction derive benefit from treatment. We would recommend objective lung function assessment with spirometry for elderly patients with respiratory symptoms. CHRIS PATTERSON, CHARLIE TEALE, LINDSEY DOW 1 Department of Medicine, Seacroft Hospital, Leeds, LS14 6UH, UK Fax: (+44) Department of Care of the Elderly, Frenchay Hospital, Bristol, BS16 1LE, UK 1. Connolly MJ. Obstructive airways disease: a hidden disability in the aged. Age Ageing 1996; 25: Dow L, Coggon D, Osmond C, Holgate ST. A population survey of respiratory symptoms in the elderly. Eur Respir J 1991; 4: BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52 (suppl. 5): S Dow L, Coggon D, Holgate ST. Respiratory symptoms as predictors of airways lability in an elderly population. Respir Med 1992; 86: Rectal examinations in elderly subjects SIR I read with interest Morgan and co-workers article on patients and doctors attitudes to rectal examination in elderly subjects [1]. This excellent article should finally put to rest the fallacy that digital rectal examination (DRE) is not performed because of patient preference. Similar attitudes were found in a slightly younger group of patients involved in a study of early detection of prostate cancer [2]. The mean age of men with prostate cancer was 63 years, 9 months, range In 2057 asymptomatic men investigated by DRE, 64 men (3.1% of those screened) were discovered to have colorectal or prostate cancer. None refused a DRE. This reiterates the acceptability of DRE and the fact that it should be included in every clinical examination as, if malignancy is diagnosed, curative or palliative therapy can be commenced. Training is the important issue. Morgan et al. reported that 65% of doctors in their study did not feel they had received sufficient training at DRE. Good training at DRE is becoming increasingly difficult due to increasing awareness of the ethical issues of consent [3]. As training in an ordered systematic approach has been shown to allow a generalist to achieve a similar accuracy to a specialist [4], the procedure needs to be actively taught and encouraged by senior staff to allow junior staff to gain adequate experience and confidence in this important area of clinical examination. JAMES S. A. GREEN Department of Urology, Royal Free Hospital, Pond Street, London, UK Fax: (+44) Morgan R, Spencer B, King D. Rectal examination in elderly subjects, attitudes of patients and doctors. Age Ageing 1998; 27:

3 2. Green JSA, Roberts EE, Turkes A et al. Preliminary results from the Gwent Pilot Study for early diagnosis of prostate cancer. Presented at the British Association of Urological Surgeons Conference, Birmingham, June Hennigan TW, Franks PJ, Hocken DB, Allen-Mersh TG. Influence of undergraduate teaching on medical students attitudes to rectal examination. Br Med J 1991; 302(6780): Varenhorst E, Berglund K, Lofman O, Pedersen K. Inter-observer variation in assessment of the prostate by digital rectal examination. Br J Urol 1993; 72: Inter-rater reliability of the clock-drawing test SIR We read with interest the review of Agrell and Dehlin on the clock-drawing test [1]. The authors discussed the feasibility, sensitivity and specificity for measuring cognitive dysfunction and dementia using several scoring systems. Unfortunately, there was no discussion of inter-rater reliability, an important feature of diagnostic tests [2]. Most studies cited did report on inter-rater reliability. There are different measures for inter-rater reliability which can complicate comparisons by reviewers and researchers who can reach different conclusions about inter-rater reliability of a test depending on the measures used. To illustrate this, we re-investigated the inter-rater reliability of two frequently used scoring methods of the clock-drawing test [3, 4]. The clock drawings of 120 consecutively referred patients were used in the outpatient memory clinic of the Academic Hospital, Nijmegen. Two raters scored independently and were blinded for the diagnostic outcome of the clock drawings according to the methods of Sunderland and Watson [3, 4]. Sunderland proposed a 10-point scoring method, in which 10 points reflect a perfect clock and lower scores reflect minor to major cognitive impairment. Watson proposed an objective method, in which the rater judges whether each of the quadrant holds three numbers. Scores range from 0 (perfect score) to 7 (worst score). In our sample, a free-drawn method was used in which the patients had to draw a circle and set the clock on ten past eleven. The inter-rater agreement was expressed both by Pearson correlation coefficient and Cohen s k. The patients mean age was 75 (SD 8), 62% were female and 64% had dementia. To familiarize ourselves with the scoring methods, a pilot on 10 randomly chosen clock drawings was performed and the differences discussed. The inter-rater reliability for Sunderland s method expressed as k was 0.58 (which is moderate), the Pearson correlation was 0.88 (P < which is high (original article 0.86 < r < 0.97). For Watson s method, the k was 0.3 (which is fair), while the Pearson correlation was 0.62 (P < 0.000) which is still quite high (original article 0.90 < r < 0.93). We were not able to reproduce the good correlation of the Watson method as reported in the original publication. This questions whether the Watson method is as objective as the authors stated. Nevertheless, a lower correlation might be explained because we used a free-drawn instead of a pre-drawn circle. In conclusion, the inter-rater reliability of scoring methods of the clock-drawing test is important. Comparison of inter-rater reliability can be difficult because different measures are used. The inter-rater reliability can be overestimated when expressed as correlation coefficients rather than k scores. HEIN VAN HOUT, SANNE BERKHOUT Department of Geriatric Medicine, University Hospital Nijmegen, Postbox 9101, 6500 HB, Nijmegen, The Netherlands Tel (+31) ; h.vanhout@czzoger.azn.nl 1. Agrell B, Dehlin O. The clock-drawing test. Age Ageing 1998; 27: Altman D. Practical Statistics for Medical Research. London: Chapman and Hall, Sunderland T, Hill JL, Mellow AM et al. Clock drawing in Alzheimer s disease. A novel measure of dementia severity. J Am Geriatr Soc 1989; 37: Watson YI, Arfken CL, Birge SJ. Clock completion: an objective screening test for dementia. J Am Geriatr Soc 1993; 41: Authors reply SIR We appreciate the comments made by Drs van Hout and Berkhout on our review of the clock-drawing test [1]. Inter-rater reliability is indeed important. We present the inter-rater reliability of the scoring systems which we presented in our overview (Table 1). Table 1. Inter-rater reliability of the scoring systems presented in the overview Reference Inter-rater reliability (r)... Sunderland et al., Mendez et al., Watson et al., (Spearman s) Förstl et al., (Pearson s) Tuokko et al., Manos and Wu, (Spearman s); (Pearson s) Ishiai et al., 1993 NR Shua-Haim et al., 1996 NR Shulman et al., 1986 NR Wolf-Klein et al., 1989 NR Friedman, 1991 NR Death et al., 1993 NR Halligan et al., 1989 NR Schenkenberg et al., 1980 NR Kokmen et al., 1991 NR NR, not reported. Watson et al., 1993: Spearman s r for two physicians 0.93; for two nurses 0.90; for a physician and a nurse

4 Ainslie and Murden, in their study of poorlyeducated people [2], scored the clock-drawing test according to Shulman et al. [3], Sunderland et al. [4] and Wolf-Klein et al. [5]. They found a k value of 0.74 for Shulman et al., 0.73 for Wolf-Klein et al. and 0.48 for Sunderland et al. Inter-rater reliability is often presented in different ways: as Pearson s correlation coefficient (assuming an approximately normal distribution), as Spearman s r (rank correlation) or simply as r and as k, which probably is the best statistical method in context [6]. BERIT AGRELL, OVE DEHLIN Geriatric Section, Department of Internal Medicine, Lund University Hospital, Lund, Sweden Fax: (+46) Agrell B, Dehlin O. The clock-drawing test. Age Ageing 1998; 27: Ainslie NK, Murden RA. Effect of education on the clock-drawing dementia screen in non-demented elderly persons. J Am Geriatr Soc 1993; 41: Shulman KI, Shedletsky R, Silver IL. The challenge of time: clockdrawing and cognitive function in the elderly. Int J Geriatr Psych 1986; 1: Sunderland T, Hill JL, Mellow AM et al. Clock drawing in Alzheimer s disease. A novel measure of dementia severity. J Am Geriatr Soc 1989; 37: Wolf-Klein GP, Silverstone FA, Levy AP, Brod MS. Screening for Alzheimer s disease by clock drawing. J Am Geriatr Soc 1989; 37: Altman D. Practical Statistics for Medical Research. London: Chapman and Hall, circumstantial evidence to support the use of antithrombotic therapy (particularly warfarin) in patients with heart failure or a low ejection fraction ( 35%). A prospective, randomized trial is required to answer this important question definitively [2]. Between 30 and 50% of patients with heart failure died from a rhythm disturbance in the SOLVD/V-HeFT II trials. The EMIAT trial showed that amiodarone reduced arrhythmic death but not all-cause mortality or cardiac mortality in survivors of a myocardial infarction with left ventricular dysfunction (left ventricular ejection fraction 40%) [3]. Physicians must weigh the adverse effects of amiodarone against any benefit. The evidence does not justify the routine use of amiodarone in survivors of myocardial infarction who have left ventricular dysfunction. Could implantation of an automatic cardiac defibrillator prevent sudden death in heart failure? Three studies (AIVD, CIDS and CASH) showed a mortality reduction of 20 40% in patients with the defibrillator compared with the best anti-arrhythmic drug therapy (Amiodarone). We cannot yet identify patients at high risk of arrhythmic death whose competing risk of death from heart failure is sufficiently low so that the benefit conferred by the implanted defibrillation could improve overall mortality [4]. In patients with heart failure refractory to conventional oral medication, the intermittent use of monitored intravenous infusions of dobutamine helps selected patients and minimizes the development of tolerance [5]. SHAHID A. KAUSAR Department of Medicine, Princess Margaret Hospital, Okus Road, Swindon SN1 4JU, UK Fax: (+44) Heart failure: a diagnostic and therapeutic dilemma in elderly patients SIR Gillespie et al. have written an excellent review [1]. However, I would like to make the following comments. About half of acute myocardial infarction survivors develop heart failure. There is controversy about the use of aspirin in heart failure. The benefit of aspirin in myocardial infarction was established in the ISIS-II trial. The benefits of aspirin on chronic coronary artery disease are less certain. Aspirin allegedly attenuates the haemodynamic effects of angiotensin converting enzyme (ACE) inhibitors. Several ACE inhibitor trials (AIRE, CONSENSUS and SOLVD) have demonstrated reduced benefits in patients taking aspirin. There was no reduction of benefit in the SAVE and TRACE trials, whereas both the AIMIS and PARIS trials suggested increased mortality of patients with heart failure on aspirin. The relation between warfarin use and survival and cardiovascular mortality was assessed in the patients enrolled in the SOLVD study which added to 1. Gillespie ND, Darbar D, Struthers AD, McMurdo MET. Heart failure: a diagnostic and therapeutic dilemma in elderly patients. Age Ageing 1998; 27: Ezeckomitz M. Anti-thrombotics for left ventricular impairment. Lancet 1998; 351: Julian DG, Camm AJ, Frangin G et al. Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349: Connolly ST. Implantable cardioverter defibrillators for whom? Lancet 1998; 352: Braunwald E. Heart disease. A text book of cardiovascular medicine, volume 1, 5th edition. Philadelphia: WB Saunders, 1996; 502. Author s reply SIR Dr Kausar raises some important points which require clarification. The merits of warfarin in patients with heart failure who are in sinus rhythm are unclear [1]. However, in patients with atrial fibrillation, the advantages of warfarin over aspirin are well established in the 328

5 prevention of stroke. In the absence of major contraindications, patients with heart failure and atrial fibrillation should be anticoagulated to prevent secondary ischaemic cerebrovascular events [2]. In the SOLVD study [3], those patients taking concomitant aspirin therapy with enalapril did not obtain an overall mortality benefit. Aspirin may reduce the beneficial effects of angiotensin converting enzyme inhibitors on exercise capacity and on haemodynamic function; these preliminary findings require further exploration. In particular, further trials are required to assess whether aspirin is predominantly helpful or harmful in patients with heart failure secondary to coronary artery disease [4]. The advent of implantable automatic cardiac defibrillators offers hope in the prevention of sudden cardiac death in some heart failure patients. However, in many frail very old patients with heart failure, quality of life and palliation of symptoms [5] are more important than prolongation of life. Nevertheless, there will be some elderly patients with heart failure for whom implantable automatic cardiac defibrillators may postpone death. The other points relate to mortality benefit and relatively invasive management. The optimum management of heart failure in elderly patients must take into account the morbidity of the condition, as the relative overall mortality benefits may be small in frail elderly people. NEIL D. GILLESPIE Department of Medicine (Ageing and Health), Ninewells Hospital and Medical School, Dundee DD1 9SY, UK Fax: (+44) Baker DW, Wright RF. Management of heart failure: IV. Anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA 1994: 272 : Cleland JGF, Cowburn PJ, Falk RH. Should all patients with atrial fibrillation receive warfarin? Evidence from randomised clinical trials. Eur Heart J 1996: 17: The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: Cleland JGF. Aspirin: does it have a role in the treatment of heart failure due to ischaemic heart disease? In Coats AJ ed. Controversies in the Management of Heart Failure. Edinburgh: Churchill Livingstone, Gibbs LE, Addington-Hall J, Gibbs JS. Dying from heart failure: lessons from palliative care. Br Med J 1998; 317: Driving safety: motivating messages SIR Physicians often have opportunities to encourage patients safe behaviours [1]. Driving accident rates are highest among young (<25 years) and senior (>55 years) drivers [2]. Older drivers reportedly use seatbelts less often [3] and equivalent crashes lead to greater physical injuries [4]. Therefore, it is important to encourage seatbelt use. Knowing how optimally to motivate this is important. Quillian [5] reported different motivations when deciding not to drive while intoxicated. Younger drivers were unwilling to drive because of legal consequences and senior drivers because of fear of physical injury. We report two observations confirming that older drivers are more motivated by concerns of physical injury and younger drivers more motivated by legal consequences. Fifteen college students (mean age = 20.1 years) and 15 seniors (mean age = 68.7 years) were shown two pairs of signs emphasizing the need to buckle seatbelts to avoid either legal or physical consequences. One pair read buckle up (picture of policeman) avoid tickets and buckle up (picture of surgery) avoid hospitals. The second pair read buckle up (picture of a judge) avoid arrest and buckle up (picture of a stretcher) avoid injury. Participants selected which sign in each pair was more likely to encourage them to fasten their seatbelts. College students predominantly selected signs emphasizing legal over physical consequences (76% versus 24%), while seniors made the opposite selection (18% versus 82%, x 2 = 5.23, P = 0.02). Next, we made signs measuring 3 2feetwhich incorporated the avoid tickets and the avoid hospitals messages. Investigators sat at two stop-signs, near a retirement village and a college campus and estimated drivers ages, then recorded whether the driver was using a seatbelt or fastened it. Sixty-six unbelted drivers, <25 years or >55 years, passed during three conditions: (i) when a sign was placed next to the stop-sign emphasizing legal consequences, (ii) when the sign emphasized physical consequences and (iii) with no sign. No-one fastened the belt when no sign was posted. Young drivers did so 9% versus 46% of the time with the physical versus legal signs, while seniors did the opposite, fastening belts 70% versus 36% of the times (x 2 = 4.00, P = 0.03). This confirms that seniors are motivated to change behaviour by concerns about physical injury, while younger drivers are more influenced by considerations of legal repercussions. This may have implications for how physicians advise older and younger patients on driving safety. BRIAN S. COX, DANIEL J. COX University of Virginia Health Sciences Center, School of Medicine, UVA Box 223, Charlottesville, VA 22908, USA Fax: (+804) Hunt DK, Lowenstein SR, Badgett RG, Steiner JF. Safety belt nonuse by internal medicine patients: a missed opportunity in clinical preventive medicine. Am J Med 1995; 98: National Highway Traffic Safety Administration. Older Drivers. The 329

6 Age Factor in Traffic Safety (report no. DOT HS ). Washington, DC: US Department of Transportation, Shinar D. Demographic and socioeconomic correlates of safety belt use. Accident Analysis Prevention 1993; 25: Waller PF. Preventing injury to the elderly. In Phillips HT, Gaylord SA eds. Aging and Public Health. New York: Springer Publishing Company, 1985; Quillian WC, Cox DJ, Kovatchev BP, Phillips C. The effects of age and alcohol intoxication on simulated driving performance, awareness and self-restraint. Age Ageing 1998; 28: