Volume 173 Issue 3

Research Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study Leon A Simons, John McCallum, Yechiel Friedlander, Michael Ortiz and Judith Simons MJA 2000; 173: 121-124 For editorial comment, see Stockwell Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Cardiology and cardiac surgery Abstract Objective: To examine the relationship between alcohol intake and survival in elderly people. Design and setting: A prospective study over 116 months of non-institutionalised subjects living in Dubbo, a rural town (population, 34 000) in New South Wales. Participants: 1235 men and 1570 women aged 60 years and over who were first examined in 1988-89. Main outcome measures: All-causes mortality; gross cost of alcohol per life-year gained. Results: Death occurred in 450 men and 392 women. Intake of alcohol was generally moderate (ie, less than 14 drinks/week). Any intake of alcohol was associated with reduced mortality in men up to 75 years and in women over 64 years. In a proportional hazards model, the hazard ratio for mortality in men taking any alcohol was 0.63 (95% CI, 0.47-0.84) and in women was 0.75 (95% CI, 0.60-0.94). Cardiovascular deaths in men were reduced from 20/100 (95% CI, 14-26) to 11/100 (95% CI, 9-13) and in women from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). The reduction in mortality occurred in men and women taking only 1-7 drinks/week -- hazard ratios, 0.68 (95% CI, 0.49-0.94) and 0.78 (95% CI, 0.61-0.99), respectively, with a similar protective effect from intake of beer or other forms of alcohol. After almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, compared with non-drinkers. The gross cost for alcohol per life-year gained if consuming 1-7 drinks/week was $5700 in men, and $19 000 in women. Conclusions: Moderate alcohol intake in the elderly appears to be associated with significantly longer survival in men 60-74 years and in all elderly women. The consumption of moderate amounts of alcohol, compared with abstention or with heavy alcohol intake, appears to be associated with reduced all-causes mortality in middle-aged subjects.1-3 This effect may be partially mediated through a reduced risk of coronary heart disease (CHD)4 and stroke.5 Some studies attribute the protection to a specific effect of wine;6,7 other studies attribute it to any type of alcohol.8In elderly people, some of this benefit from moderate alcohol intake may be negated by mortality from other causes.9 In a prospective study of men and women aged 65 years and over in the United States (Established Populations for Epidemiologic Studies of the Elderly), alcohol intake under 21 drinks/week was associated with a 30%-40% lower all-causes mortality in two cohorts, but with no influence in a third cohort.10 In Australian men and women aged 60 years and over with 77 months' follow-up, the intake of 1-7 drinks/week was associated with a 22%-25% reduction in all-causes mortality, although this reduction did not achieve statistical significance.11 We have examined the relationship between alcohol intake and survival in this Australian cohort during a more extended follow-up of 116 months. We present the results and include an economic analysis of moderate alcohol intake. Methods Dubbo Study The Dubbo Study is an ongoing prospective examination of cardiovascular and other diseases in an elderly Australian cohort first examined in 1988-89. All non-institutionalised residents of Dubbo, New South Wales, born before 1930 were eligible; participation rate was 73% (1235 men and 1570 women). Methods and measures have already been described in detail.12,13 The baseline examinations comprised demographic, psychosocial and standard cardiovascular risk assessments, including examination of fasting blood samples. Alcohol usage Questions on alcohol usage were those asked in the National Heart Foundation Risk Factor Prevalence Study,14 and yielded an approximation of usual alcohol intake coded as zero, 1-7, 8-14, 15-28 and more than 28 drinks/week (referring to a standard drink containing 10 g of alcohol). Specific intakes of beer, wine and spirits were not separately sought, but subjects were asked whether they normally drank beer or not, allowing a separation of drinking behaviour into beer and "other". Survival analysis Outcomes from August 1988 to 31 December 1998 were included in the analysis, a median 116 months' follow-up. Hospitalisation and death records were monitored continuously, and postal surveys were conducted every two years to confirm vital status. The survey in 1997 successfully traced more than 98% of surviving participants. Records were coded according to the International classification of diseases, ninth revision, clinical modification (ICD-9-CM). The independent contribution of any risk factor to mortality was examined in a Cox proportional hazards model. Point estimates and 95% CIs for the relative hazard of death were calculated from the regression coefficients (presented as hazard ratio, a measure of relative risk). The models included categories of alcohol intake as described above, and, where relevant, a categorical term describing whether a subject normally drank beer or "other" (ie, wine/spirits). The proportional hazards model assumes constant relative hazard over the length of follow-up. This assumption was confirmed for each model by a plot of log-minus-log survival, demonstrating parallel curves over all categories of alcohol intake. Statistical analyses were conducted using SPSS for Windows NT.15 Economic analysis A weighted alcohol acquisition cost per week using the midpoint of the intake ranges was calculated for each alcohol intake stratum and for each sex using 1999 Dubbo club prices. Individuals were assumed to remain in their initial consumption strata over the whole time period. Survival curve data from the Cox model were used to calculate total expenditure on alcohol, as well as survival benefit for each stratum of intake. An incremental analysis (difference in cost/difference in benefit) was conducted using the no-alcohol-consumption stratum as the reference. This yielded an estimate of the gross cost per life-year gained. Although the study collects hospitalisation records, hospitalisation costs were not available and a net cost per life-year gained could not be estimated. Ethical approval The study was approved by the institutional ethics committees at St Vincent's Hospital, Sydney, the University of New South Wales and the Australian National University. All participants gave informed, written consent. Results Pattern of alcohol intake The pattern of alcohol intake and its clinical associations have been fully documented in an earlier report.11 The pattern of alcohol intake, by quantity and type, is shown in Box 1. On a day when alcohol was consumed, 40% of all men and 45% of all women took one or two drinks, 23% and 7% took three or four drinks, and 15% and 1%, respectively, took five or more drinks. All-causes mortality Death occurred in 450 men (36%) and 392 women (25%). Consumption of more than 14 drinks/week was uncommon. Hence, where relevant, the use of alcohol has been grouped into zero use and any use. Alcohol intake: Age-specific all-causes mortality by alcohol intake is presented in Box 2. Alcohol use in men appeared to be associated with reduced mortality up to age 74 years, but not beyond. In women, its use was associated with reduced mortality in all groups older than 64 years. Predictors of all-causes mortality: The independent contribution of alcohol to all-causes mortality was explored in men 60-74 years and in all women in proportional hazards models which adjusted for the presence of major demographic, psychosocial and cardiovascular variables at study entry. The significant predictors of all-causes mortality are summarised in Box 3. (Alcohol intake was not a significant predictor of mortality in men aged more than 74 years.) Any alcohol intake was significantly associated with reduced all-causes mortality in both sexes. Quantity or type of alcohol intake: The relationship between quantity or type of alcohol intake and all-causes mortality in the proportional hazards model is presented in Box 3. The risk of mortality was significantly reduced at all levels of alcohol intake, except in women taking 15-28 drinks/week (representing only 3% of women in the study). A similar degree of reduction in all-causes mortality was observed at all levels of alcohol intake. The protection observed was broadly similar in those using beer versus wine/spirits, although this only reached statistical significance for beer consumption. Pattern of alcohol intake: In a subsequent model, the quantity of alcohol consumed per week was replaced by a variable denoting the usual number of drinks taken on a given day, a measure of the pattern of drinking. Using zero intake as the reference group, the hazard ratio in men with a consumption of one or two drinks on a given day was 0.64 (95% CI, 0.46-0.89), with three or four drinks 0.68 (95% CI, 0.47-0.98), and with five or more drinks 0.69 (95% CI, 0.45-1.06). The corresponding hazard ratios in women were 0.74 (95% CI, 0.59-0.93), 0.68 (95% CI, 0.38-1.22) and 1.38 (95% CI, 0.58-3.29) (there were only 17 women in this group). Hazard curves: The hazard curves calculated from the proportional hazards models in men and women are presented in Box 4. By the end of almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, than their counterparts taking no alcohol. Specific causes of death: Cardiovascular death (ie, CHD and stroke) was reduced from 20/100 (95% CI, 14-26) in non-drinkers to 11/100 (95% CI, 9-13) in men taking any alcohol. The corresponding reduction in cardiovascular death in women was from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). Deaths attributed to any cancer were unchanged in men (6/100 [95% CI, 3-9] versus 7/100 [95% CI, 5-9]) and in women (4/100 [95% CI, 2-6] versus 5/100 [95% CI, 3-7]). Gross cost for alcohol per life-year gained From the number of life-years added to survival for each quantity of intake, we have estimated the gross cost for alcohol per life-year gained. In men 60-74 years and in women 60 years and over taking 1-28 drinks/week, the respective costs were $13 000 and $31 000 per life-year gained. Since much of the benefit from alcohol intake was observed at a moderate intake of only 1-7 drinks/week, the respective costs at this intake were $5700 and $19 000 per life-year gained. Discussion In this well-defined, community-based sample of rural elderly Australians, alcohol intake could be described as moderate rather than heavy.11 Our results confirm that any intake of alcohol is associated with significantly reduced all-causes mortality in men 60-74 years and in all elderly women, consistent with our previous report at 77 months' follow-up.11 Statistical significance has now been reached due to the greater number of deaths and increased statistical power. Absolute death rates in men were substantially higher than in women, especially in the "young old". This would account for the greater average survival advantage shown in Box 4 (7.6 months versus 2.7 months). Equivalent reductions in mortality occurred at 1-7 drinks/week and at higher intakes. In men there was no evidence of a differential effect between 1-2 drinks on a given day and an intake of five or more drinks on a given day. Not all studies have documented an association between all-causes mortality and alcohol intake.16,17 The reduction in CHD and stroke mortality associated with alcohol use we observed is consistent with findings of previous reports,8,18,19 as well as those of recent reports in large middle-aged cohorts from the United States.4,5,20 These data are gradually causing health authorities to reconsider public policy on moderate alcohol intake, say 1-7 drinks/week, in the prevention of future morbidity and mortality.21 Studies in younger populations indicate a "U"- or "J"-shaped relationship between alcohol intake and all-causes mortality.2 This has not been a general finding in the elderly, possibly because these cohorts contain an excess of "healthy survivors".10 It is surprising that we could find no relationship between alcohol intake and mortality in men aged over 74 years, but it is plausible that very elderly men lose the benefit of alcohol intake because they become subject to competing causes of mortality.9 There is a potential for misclassification of alcohol intake between zero and low intake because of under-reporting. This would diminish any apparent relative benefit of alcohol intake on all-causes mortality. Hence, our statistically significant findings may represent a minimum estimate of the benefit of moderate alcohol intake. We have demonstrated essentially a "threshold effect" between alcohol intake and all-causes mortality in either sex. Protection does not improve greatly as alcohol intake increases further (Box 3). Thus, under-reporting would then have less impact on our findings. This threshold effect is important, particularly if we were to move to a public health position of suggesting that abstainers should begin to imbibe! The economic findings take no account of any changes in healthcare costs arising downstream through the benefits or otherwise of alcohol intake. What we regard as an acceptable cost per life-year gained is arbitrary, but it is informative to compare our calculated costs with, for example, recently published gross costs for the use of simvastatin in patients with established CHD, with survival increased by around 20%.22 Assuming such patients receive lifetime therapy with simvastatin from their mid-50s, the gross cost per life-year gained in the UK population would be £5100 (or about $13 000). Although one is comparing unrelated "therapy", moderate alcohol intake, at least in older men, may turn out to be a popular and cost-effective means of improving survival which does not require government subsidy! The relative merits of wine versus other forms of alcohol consumption remain controversial. Data from France6 and Denmark7 highlight specific benefits of wine, and this has generated a new research effort to identify which components of wine, apart from alcohol, may be the most beneficial. Antioxidants are among the most prominent suggestions.23 Others consider that alcohol in any form gives protection against cardiovascular disease,8 largely through its effect in raising high density lipoprotein (HDL) cholesterol levels.11 In Dubbo, the quantity of alcohol intake was highly correlated with HDL cholesterol (r = 0.32, P < 0.001 and r = 0.23, P < 0.001 in men and women, respectively). Other suggested mechanisms for cardiovascular protection include favourable effects of alcohol on thrombotic and fibrinolytic pathways, reduced insulin resistance and improved endothelial function through increased nitric oxide production.5 Alcohol may also influence survival in ways which currently defy measurement: regular alcohol intake may reflect a special lifestyle integrated with less tangible factors.21 Although excess alcohol intake is undoubtedly toxic to the central nervous system, recent studies suggest that a moderate intake may reduce the risk of dementia. In a study of elderly French people 65 years and over, appropriately from Bordeaux, the rate of hospitalisation for dementia in non-drinkers over three years was 4.9/100, but only 3.9/100 in those taking any alcohol (with a more striking effect on the risk of Alzheimer's disease).24 During 116 months' follow-up in the Dubbo population, the respective rates of hospitalisation for dementia were 4.3/100 and 2.5/100 (P < 0.01). It is premature to promote the use of alcohol for prevention of dementia, but the 21st century may witness a completely new role for alcohol in health. Acknowledgements The Dubbo Study is supported in part by grants from the National Health and Medical Research Council of Australia, Astra Pharmaceuticals Pty Ltd, Amrad Pharmaceuticals Pty Ltd, Bristol-Myers Squibb Australia Pty Ltd, Merck Sharp & Dohme Australia Pty Ltd, Parke Davis Pty Ltd and Pfizer Pty Ltd. We acknowledge the dedication of the Dubbo Nurse-Manager Kerrie Pearson, the assistance of Gina Brinsmead in economic analysis and Helen Adams in preparation of the manuscript. References Klatsky AL, Armstrong MA, Friedman DD. Alcohol and mortality. Ann Intern Med 1992; 117: 646-654. Holman CDJ, English DR, Milne E, Winter MG. Meta-analysis of alcohol and all-cause mortality: a validation of NHMRC recommendations. Med J Aust 1996; 164: 141-145. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997; 337: 1705-1714. Albert CM, Manson JE, Cook NR, et al. Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation 1999; 100: 944-950. Berger K, Ajani UA, Kase CS, et al. Light-to-moderate alcohol consumption and the risk of stroke among US male physicians. N Engl J Med 1999; 341: 1557-1564. Renaud S, Geuguen R, Siest G, Salamon R. Wine, beer, and mortality in middle-aged men from Eastern France. Arch Intern Med 1999; 159: 1865-1870. Gronbaek M, Deis A, Sorensen TIA, et al. Mortality associated with moderate intakes of wine, beer or spirits. BMJ 1995; 310: 1165-1169. Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine or spirits? BMJ 1996; 312: 731-735. Van de Water HA, Boshuizen HC. The impact of substitute morbidity and mortality on public health policies. Leiden: TNO Prevention and Health, Division of Public Health and Prevention, 1995. Scherr PA, LaCroix AZ, Wallace RB, et al. Light to moderate alcohol consumption and mortality in the elderly. J Am Geriatr Soc 1992; 40: 651-657. Simons LA, Friedlander Y, McCallum J, Simons J. Alcohol intake and survival in the elderly: a 77 month follow-up in the Dubbo Study. Aust N Z J Med 1996; 26: 662-670. Simons LA, McCallum J, Friedlander Y, et al. Dubbo Study of the elderly: sociological and cardiovascular risk factors at entry. Aust N Z J Med 1991; 21: 701-709. Simons LA, McCallum J, Friedlander Y, Simons J. Predictors of mortality in the prospective Dubbo Study of Australian elderly. Aust N Z J Med 1996; 26: 40-48. Risk Factor Prevalence Study Management Committee. Risk Factor Prevalence Study: Survey No 3 1989. Canberra: National Heart Foundation Australia and Australian Institute of Health, 1990. SPSS for Windows NT [computer program], version 9.0. Chicago, Ill: SPSS Inc, 1999. Leino EV, Romelsjo A, Shoemaker C, et al. Alcohol consumption and mortality. II. Studies of male populations. Addiction 1998; 93: 205-218. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of Scottish men with 21 years follow up. BMJ 1999; 318: 1725-1729. Hennekens CH, Willett W, Rosner B, et al. Effects of beer, wine and liquor in coronary deaths. JAMA 1979; 242: 1973-1974. Stampfer MJ, Colditz GA, Willett WC, et al. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988; 319: 267-273. Sacco RL, Elkind M, Boden-Albala B, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60. Hommel M, Jaillard A. Alcohol for stroke prevention? N Engl J Med 1999; 341: 1605-1606. Pickin DM, McCabe CJ, Ramsay LE, et al. Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of treatment. Heart 1999; 82: 325-332. Frankel EN, Kanner J, Germann JB, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993; 341: 454-457. Orgogozo J-M, Dartigues J-F, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris) 1997; 153: 185-192. (Received 23 Dec 1999, accepted 10 Apr 2000) Authors' details University of New South Wales Lipid Research Department, St Vincent's Hospital, Sydney, NSW. Leon A Simons, MD, FRACP, Associate Professor of Medicine; Judith Simons, MACS, Analyst-Programmer. Faculty of Health, University of Western Sydney MacArthur, Sydney, NSW. John McCallum, DPhil, Professor and Dean. Department of Social Medicine, Hebrew University - Hadassah Hospital, Jerusalem, Israel. Yechiel Friedlander, PhD, Associate Professor in Epidemiology. Pfizer Pty Ltd, Sydney, NSW. Michael Ortiz, PhD, Health Outcomes Manager. Reprints will not be available from the authors. Correspondence: Professor L A Simons, Lipid Research Department, St Vincent's Hospital, Darlinghurst, NSW 2010. l.simonsATnotes.med.unsw.edu.au Make a comment Back to text 2: Age-specific all-causes mortality rate and alcohol intake during 116 months' follow-up of subjects 60 years and over. Data are mortality rates per 100 subjects (95% CI and number of subjects in each group in parentheses) Men Women Zero alcohol Any alcohol Zero alcohol Any alcohol 60-64 y 65-69 y 70-74 y 75-79 y 80+ y All ages 26 (17-35) (88) 37 (24-50) (54) 57 (45-69) (65) 51 (35-67) (37) 83 (68-98) (23) 44 (38-50) (267) 17 (13-21) (326) 26 (21-31) (266) 41 (34-48) (184) 64 (55-73)(120) 83 (74-92) (63) 34 (31-37) (959) 9 (5-13) (193) 22 (16-28) (172) 31 (24-38) (154) 45 (36-54) (121) 72 (63-81) (104) 31 (28-34) (744) 10 (7-13) (288) 14 (9-19) (191) 11 (6-16) (166) 36 (27-45) (107) 54 (42-66) (68) 20 (17-23) (820) Back to text 3: Proportional hazards model of all-causes mortality and alcohol intake in elderly subjects Hazard ratio (95% CI) Men 60-74 years Women 60+ years Significant predictors of all-causes mortality Any alcohol intake Age (/year) Current smoker Ex-smoker Prior stroke Blood pressure medication Diabetes Atrial fibrillation Poor expiratory flow 0.63 (0.47-0.84) 1.07 (1.04-1.11) 2.81 (1.90-4.16) 1.76 (1.26-2.46) 1.58 (1.03-2.42) 1.54 (1.16-2.06) 1.99 (1.38-2.87) -- 1.53 (1.09-2.17) 0.75 (0.60-0.94) 1.08 (1.06-1.10) 1.74 (1.22-2.49) -- -- -- 2.06 (1.46-2.92) 2.77 (1.65-4.64) 2.00 (1.43-2.79) Relationship of quantity or type of alcohol to all-causes mortality Drinks/week Nil 1-7 8-14 15-28 >28 1.00 0.68 (0.49-0.94) 0.58 (0.39-0.85) 0.62 (0.40-0.95) 0.56 (0.33-0.96) 1.00 0.78(0.61-0.99) 0.66 (0.45-0.97) 0.67 (0.29-1.55) Alcohol type Nil Beer Wine/spirits 1.00 0.62 (0.46-0.84) 0.70 (0.44-1.12) 1.00 0.64 (0.47-0.86) 0.85 (0.66-1.11) The reference category for alcohol usage was zero intake. Other variables in the models were body mass index, family history of coronary heart disease (CHD), prevalent CHD, blood pressure, lipid levels, self-rated health, and physical disability. Poor expiratory flow refers to peak expiratory flow tertile I. Back to text Back to text

Leon A Simons · John McCallum · Yechiel Friedlander · Michael Ortiz · Judith Simons

Research A randomised crossover trial of chemotherapy in the home: patient preferences and cost analysis Danny Rischin, Michelle A White, Jane P Matthews, Guy C Toner, Kathryn Watty, Anthony J Sulkowski, Jan L Clarke and Lois Buchanan MJA 2000; 173: 125-127 Abstract - Methods - Results - Discussion - References - Authors' details - - More articles on Oncology Abstract Objectives: To determine patient preferences and cost differences between home-based and hospital-based chemotherapy. Design: Randomised crossover trial. Setting: A tertiary cancer hospital in Melbourne, Victoria. Participants: 20 patients who required chemotherapy suitable for administration at home. Interventions: Patients were assigned at random to receive their first chemotherapy treatment in either the home or the hospital and the second treatment in the alternative setting. Main outcome measures: Patient preference, costs. Results: There was universal agreement by the 20 patients in the randomised trial that home-based chemotherapy was the preferred option (P < 0.0001). No problems were nominated by the patients as being associated with home-based chemotherapy. Home-based treatment was estimated to result in an increased cost of $83 (P = 0.0002) for each chemotherapy treatment compared with hospital-based treatment. Reported advantages for chemotherapy in the home included the elimination of travel, reduction in treatment-associated anxiety, reduction in the burden on carers and family, and the ability to continue other duties. There were no significant complications associated with administration of chemotherapy in the home. Conclusions: Patients prefer home-based chemotherapy to hospital-based treatment. The future of chemotherapy-in-the-home programs in Australia will depend on whether patient preferences are deemed to offset any potential increase in costs. Patients with cancer who require treatment with chemotherapy will experience major changes in lifestyle and overall well-being. Some intravenous chemotherapy regimens require frequent visits to hospital to receive treatment. This may be time-consuming and inconvenient for a patient, and may also disrupt the lives of other family members and carers. The concept of home-based therapy is not new,1-3 but there have been few reports on chemotherapy-in-the-home programs, and these have had a different emphasis from our study (eg, costs [in a US paediatric population];4 costs and safety [in a retrospective review of an Australian adult population]5). We performed a randomised crossover trial, the aim of which was to compare (i) patient preference for hospital-based versus home-based chemotherapy; and (ii) the cost of therapy administered in hospital versus that in the home. Methods Patient eligibility Patients were considered eligible if they met the following criteria: they were to receive chemotherapy that was suitable to be given at home; their first two treatments were planned to be identical; they had not received chemotherapy in the preceding 12 months; they lived in an area that was geographically suitable for treatment at home; and they were aged 18 years or over. Patients gave written informed consent and the study was approved by the ethics committee of the Peter MacCallum Cancer Institute. Study design At enrolment, patients were randomly assigned to receive their first chemotherapy treatment in hospital and the second at home, or their first treatment at home and the second in hospital. They were assigned according to a computer-generated randomisation chart, using an allocation scheme based on a biased coin design.6Chemotherapy treatment refers to the first two administrations of chemotherapy. Following completion of the first two treatments, patients filled out a questionnaire regarding the two different locations of therapy. Questions focused on (i) patients' preference for where to receive their remaining chemotherapy after completing their two study treatments; and (ii) any perceived difficulties or advantages of treatment in hospital or in the home. Chemotherapy nurse specialists who also worked in the chemotherapy day ward at the hospital administered all home chemotherapy treatments. Patients were reviewed by a doctor before each chemotherapy cycle. Cost assessment Cost comparisons for hospital-based versus home-based therapy were made specifically from the perspective of the treating hospital, not the patient or society in general. Costs were estimated using Transition software (Eclipsys Transition Systems, Boston, MA), which distributes direct and indirect costs for an entire financial year between patient episodes on the basis of the services received. It was decided to compare only those components of the cost for which there could be a genuine difference to the hospital attributable to the site of delivery of the chemotherapy. Thus, costs related to patient records, allied health, medical staff and pharmacy were excluded. All overheads associated with the chemotherapy-in-the-home program, including vehicle costs and travelling time, were apportioned by Transition to nursing costs on the basis of time spent with each patient. Similarly, hospital overheads were apportioned on the basis of nursing times. The cost of providing a single meal was included in the hospital costs. Statistical methods A target sample size of 20 eligible patients with identical chemotherapy for their first two treatments was chosen, to provide 84% power to test the null hypothesis that no one setting is preferred versus the alternative hypothesis that at least 85% of patients prefer one setting over the other, using a two-sided test of significance at a significance level of 0.05. To determine if significantly more patients preferred treatment at home rather than in hospital, or vice versa, the proportion of patients preferring to have their third treatment in the same location as their first treatment was compared between the two randomisation arms using Fisher's exact test for 2 x 2 contingency tables. This test is valid even if there are "period" effects -- that is, if patients tolerate their second chemotherapy treatment better than their first, or vice versa.7 Standard methods for a 2 x 2 crossover trial7 were used to compare costs of chemotherapy in hospital with costs in the home, and costs between the first and second chemotherapy given ("period" effects), after ensuring there were no significant carryover effects. (Carryover effects were tested by comparing the sum of the costs in the home and hospital for patients in the "hospital first" arm with patients in the "home first" arm.) Statistical significance and 95% confidence intervals (CIs) were estimated from the means and standard errors assuming a Student's t-distribution. Two-sided P-values have been given throughout. All statistical tests were carried out using Stat Xact 4 (CYTEL Software Corporation, Cambridge, MA, 1998) and Microsoft Excel (Microsoft Corporation, Redmond, WA, 1996) software. Results Patient selection and profile The trial accrued the target 20 patients, out of a total of 64 registered on the chemotherapy-in-the-home program, between February 1996 and March 1997 (see Box 1). Patient demographics are shown in Box 2. Patient preferences When asked where they would have preferred to receive their first two treatments if they had had their time again, 70% of patients expressed a preference for having both treatments at home, while none said they would have preferred to have both treatments in hospital (Box 3). Patients were then asked to nominate their preferred site for the remaining treatments (the primary endpoint of the trial). All 20 patients (100%; 95% CI, 83%-100%) preferred to have their remaining therapy given at home (P < 0.0001). None of the patients in the trial reported concerns with chemotherapy being given in their home; however, four (20%) reported concerns with treatment in hospital, relating to transport difficulties and waiting times. Eighteen (90%) of the patients felt there were advantages with treatment in the home. The reasons given included convenience; avoidance of travel and parking problems (particularly not having to travel while feeling unwell); reduction in treatment-associated anxiety; not burdening their carers and family; and being able to continue other duties, such as caring for their dependants. Only one patient felt there were specific advantages to chemotherapy in the hospital. This patient felt it was good to see other people who were worse off. No major complications of chemotherapy administration (eg, hypersensitivity reactions or extravasation) were reported. Costing Overall, chemotherapy in the home was associated with an estimated average increased cost of $83 (95% CI, $46-$120; P = 0.0002) relative to the cost of chemotherapy in the hospital. The average cost of the first treatment was estimated to be $57 more than the cost of the second (95% CI, $20-$94; P = 0.0044). There was no carryover effect (P = 0.16). Discussion This study has demonstrated that patients have an overwhelming preference for home-based therapy. Clearly, home-based therapy is not possible, or indeed appropriate, for all patients. Patients living outside designated geographical areas or having special needs that can be met in the hospital setting (eg, need for an interpreter) would be more easily treated at the hospital.8 Complex or prolonged chemotherapy regimens or those associated with a risk of an immediate serious complication are more appropriately administered in the hospital day ward setting. Nevertheless, many commonly administered chemotherapy regimens are suitable for administration in the home, and this study clearly demonstrates that, given the choice, patients prefer to have such treatments at home. While in our study the cost of home-based treatment was on average $83 higher than the cost of hospital-based therapy, this estimate did not include costs to the patient (such as travelling costs, lost time for the patient or carers, and childcare costs). These could all have made the hospital episode more costly relative to the home episode. Furthermore, given that the cost per visit for any chemotherapy-in-the-home program is dependent on the throughput of patients and the geographical spread of the patients, an increase in the frequency of home visits or a more limited geographical spread of patients might further reduce the difference between home and hospital costs. Unlike some other hospital-in-the-home programs, chemotherapy in the home does not necessarily result in cost savings to the administering hospital, as treatment in the hospital does not require overnight admission. The future of chemotherapy-in-the-home programs in Australia will depend on how governments, hospital administrators, oncologists and nurses balance the overwhelming patient preference for treatment at home with any potential increase in costs. References Grayson ML, Silvers J, Turnidge J. Home intravenous antibiotic therapy. A safe and cost effective alternative to inpatient care. Med J Aust 1995; 162: 249-253. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 1996; 334: 682-687. Bielory L, Long GC. Home health care costs: intravenous immunoglobulin home infusion therapy. Ann Allergy Asthma Immunol 1995; 74(3): 265-268. Close P, Burkey E, Kazak A, et al. A prospective, controlled evaluation of home chemotherapy for children with cancer. Pediatrics 1995; 95: 896-900. Lowenthal RM, Piaszczyk A, Arthur GE, et al. Home chemotherapy for cancer patients: cost analysis and safety. Med J Aust 1996; 165: 184-187. Wei LJ, Lachin JM. Properties of the urn randomization in clinical trials. Control Clin Trials 1988; 9: 345-364. Jones B, Kenward MG. Design and analysis of cross-over trials. London: Chapman and Hall Ltd, 1989. Zalcberg JR, Siderov J, Petty M. Outpatient chemotherapy: there's no place like home - sometimes. Med J Aust 1996; 165: 182. (Received 11 Oct 1999, accepted 24 May, 2000) Authors' details Peter MacCallum Cancer Institute, Melbourne, VIC. Danny Rischin, MB BS(Hons), FRACP, Consultant Medical Oncologist, Division of Haematology and Medical Oncology; Michelle A White, MB BS(Hons), FRACP, Clinical Fellow, Division of Haematology and Medical Oncology; Jane P Matthews, BSc(Hons), PhD, AStat, Director, Statistical Centre; Guy C Toner, MD, BS, FRACP, Head of Medical Oncology, Division of Haematology and Medical Oncology; Kathryn Watty, RN, RM, Clinical Nurse Consultant, Division of Nursing; Anthony J Sulkowski, RN, BEd, Clinical Nurse Consultant, Division of Nursing; Jan L Clarke, RN, Clinical Nurse Consultant, Division of Nursing; Lois Buchanan, RN, RM, Clinical Nurse Consultant, Division of Nursing. Reprints will not be available from the authors. Correspondence: Dr D Rischin, Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Melbourne, VIC 8006. drischinATpetermac.unimelb.edu.au Make a comment Click in box for larger version Back to text 2: Patient demographics, by randomisation arm (first chemotherapy treatment given at hospital vs first treatment at home). Values are number of patients unless otherwise stated Hospital first Home first Total (%) Sex Male Female 1 8 4 7 25% 75% Age Median (years) Range (years) 40-49 50-59 60-69 70 61 47-71 0 2 1 5 1 59 26-69 1 4 1 5 0 -- -- 5% 30% 10% 50% 5% Diagnosis Breast cancer Colon cancer Non-Hodgkin's lymphoma Pancreatic cancer 5 3 0 1 5 5 1 0 50% 40% 5% 5% Chemotherapy CMF(P)* 5-FU† ± folinic acid or levamisole CHOP‡ 5 4 0 5 5 1 50% 45% 5% Support at home Spouse/parent Parent Son/daughter Other Not specified 4 1 3 0 1 7 0 1 3 0 55% 5% 20% 15% 5% * Cyclophosphamide, methotrexate, 5-fluorouracil ±prednisolone. † 5-Fluorouracil. ‡Cyclophosphamide, doxorubicin, vincristine and prednisolone. Back to text 3: Preferred location for chemotherapy treatments, by randomisation arm (first chemotherapy treatment given at hospital vs first treatment at home). Values are number of patients Hospital first Home first Total (%) For first 2 treatments Both at home First at home, second at hospital No preference First at hospital, second at home Both at hospital 7 0 1 1 0 7 2 1 1 0 14 (70%) 2 (10%) 2 (10%) 2 (10%) 0 For subsequent treatments Home Hospital 9 0 11 0 20 (100%) 0 Back to text

Danny Rischin · Michelle A White · Jane P Matthews · Guy C Toner · Kathryn Watty · Anthony J Sulkowski · Jan L Clarke · Lois Buchanan

Ethics Ethical issues in placebo-controlled trials in Alzheimer's disease Robert D Goldney and Brian F Stoffell MJA 2000; 173: 147-148 The use of placebos and the dubiousness of patients' ability to give informed consent give rise to various ethical concerns The use of placebos in clinical drug trials is the most conclusive method of elucidating the effectiveness of new medications. However, it has long been recognised that there are significant ethical issues with such trials, as some patients will be given no specific therapy.1,2Few would argue against the use of placebos in drug trials when there are no effective treatments available. However, there comes a time in the treatment of most illnesses when one or other treatment is recognised as effective. It is then that ethical questions arise in the use of placebos in evaluating other new treatments for the same condition. For example, it is difficult to justify the use of placebos in trialling new medications for treating depression. Gold standards such as tricyclic antidepressants, or the now well-established selective serotonin reuptake inhibitors, are generally used as benchmarks in studies examining the efficacy of new antidepressants. How well established do new treatments have to be before they themselves become the standard against which other new drugs should be investigated rather than subjecting patients to the risk of having no treatment at all? This situation is addressed in Section 12.4 of the recently published National Health and Medical Research Council (NHMRC) Statement on ethical conduct in research involving humans,3 which states: "The use of a placebo alone or the incorporation of a non-treatment control group is ethically unacceptable in a controlled trial where: (a) other available treatment has already been clearly shown to be effective; and (b) there is risk of significant harm in the absence of treatment. If there is genuine uncertainty about the net clinical benefit of a treatment, a placebo controlled trial or a trial with a no-treatment arm may be considered." This is clearly relevant in the emergence of approved treatments for Alzheimer's disease, for which new agents are now available.4 The two drugs available in Australia, tacrine and donepezil, have proven effective in double-blind randomised-controlled trials.5,6 This level of evidence (E2 or Level II)7 was considered sufficient for these drugs to have been approved for marketing by the Commonwealth Therapeutic Goods Administration. That being so, one would assume that at least criterion (a) above has been met. Criterion (b) above could be assumed if one accepts that Alzheimer's disease is a progressive condition. This would be significant if one were proposing a prolonged trial to demonstrate the efficacy of a medication, even if an established drug may only halt the process of decline. This has, for example, become relevant in the initial treatment of schizophrenia. One study showed more severe negative and positive symptoms in schizophrenia associated with a delay in the initiation of treatment, not attributable to poorer premorbid functioning actually delaying the commencement of treatment.8 Another study showed that cortical volume deficits were progressive, but that after treatment they appeared to be static or even partly reversible.9 The analogy between these findings for schizophrenia and the situation with Alzheimer's disease is compelling. The role of plaques containing amyloid beta-peptide (Abeta) in Alzheimer's disease has been elucidated, and there is now evidence of a correlation between elevated levels of Abeta plaques and cognitive decline.10 As the cholinesterase inhibitors tacrine and donepezil influence the formation of Abeta plaques,11 these drugs may be truly disease modifying. Naturally, such findings add to the debate about the wisdom of using placebo controls when a treatment is available. These issues in relation to Alzheimer's disease have been discussed recently in the international literature.12-18 Knopman et al noted that "the design of clinical trials must evolve as new therapies become available", and stated that "there is now a compelling case for alternatives to trials that include a treatment arm with no active therapy".14 In similar vein, Kawas et al concluded that "As new and more effective treatments emerge, the ethical framework for placebo use in AD (Alzheimer's Disease) studies will require frequent re-examination".17 This is of particular relevance to Alzheimer's disease, as the question arises as to whether or not the patients themselves are able to give informed consent. This is also addressed in the NHMRC Statement on ethical conduct in research involving humans,3 under Sections 5.2 and 5.3, which state: "Consent to participation in research by a person with an intellectual or mental impairment must be obtained from: (a) the person with the intellectual or mental impairment whenever the person is of sufficient competence and, where the impairment is temporary or recurrent, at a time when the impairment does not prevent the person giving or refusing consent; or failing that (b) the person's guardian, or an authority or other organisation or person having that responsibility at law. A Human Research Ethics Committee (HREC) must not approve, and consent cannot be given for, research which is contrary to the best interests of the person with the intellectual or mental impairment." The task of ethics committees is particularly onerous in light of these recommendations. The very fact that drugs have been approved by the Therapeutic Goods Administration must again be seen as compelling in terms of there being a treatment available which should be provided for patients in their potential best interests. However, although tacrine and donepezil have been approved for marketing, they are expensive and as yet not subsidised by the Pharmaceutical Benefits Scheme. This raises the question of whether or not it is ethical for those who will not be able to afford to continue with the treatment to be placed in a trial merely in the hope that they may be given the active drug and gain some temporary benefit. It is doubtful whether this is an ethically acceptable argument for allowing participation in such trials, especially as proxies will usually be giving consent, and their legitimate concern for the patient may give this "opportunity for an expensive therapy" too much moral weight. Institutional ethics committees will be increasingly confronted with these challenges in the coming years. It behoves all such committees to carefully consider these points, bearing in mind that there may also be changes in community attitudes about these issues. Robert D Goldney MD, Professor of Psychiatry, University of Adelaide The Adelaide Clinic, Gilberton, SA rgoldneyATmedicine.adelaide.edu.au Brian F Stoffell PhD, Director of Medical Ethics Flinders Medical Centre Flinders University of South Australia, Adelaide SA Reprints: Professor R D Goldney, The Adelaide Clinic, 33 Park Terrace, Gilberton, SA 5081 Haegerstam G, Huitfeldt B, Nilsson BS, et al. Placebo in clinical drug trials -- a multidisciplinary review. Methods Find Exp Clin Pharmacol 1982; 4: 261-278. Klerman GL. Scientific and ethical considerations in the use of placebo controls in clinical trials in psychopharmacology. Psychopharmacol Bull 1986; 22: 25-29. National Health and Medical Research Council. National statement on ethical conduct in research involving humans. Canberra: NHMRC, 1999. Brodaty H, Sachdev P. Drugs for the prevention and treatment of Alzheimer's disease. Med J Aust 1997; 167: 447-452. Knapp MJ, Knopman DS, Solomon PH, et al. A 30-week randomised controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994; 271: 985-991. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology 1998; 50: 136-145. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, 1999. Haas GL, Garratt LS, Sweeney JA. Delay to first antipsychotic medication in schizophrenia: impact on symptomatology and clinical course of illness. Psychiatr Res 1998; 32: 151-159. Keshavan MS, Haas GL, Kahn CE, et al. Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? Psychiatr Res 1998; 32: 161-167. Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000; 283: 1571-1577. Emilien G, Beyreuther K, Masters CL, Maloteaux JM. Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 2000; 57: 454-459. Mariani L, Ventresca GP. Is the placebo still ethically acceptable and scientifically useful in clinical drug experimentation? Clin Ther 1996; 147: 595-598. Whitehouse PJ. Future prospects for Alzheimer's disease therapy: ethical and policy issues for the international community. Acta Neurol Scand Suppl 1996; 165: 145-149. Knopman D, Kahn J, Miles S. Clinical research designs for emerging treatments for Alzheimer disease: moving beyond placebo-controlled trials. Arch Neurol 1998; 55: 1425-1429. Karlawish JH, Whitehouse PJ. Is the placebo control obsolete in a world after donepezil and vitamin E? Arch Neurol 1998; 55: 1420-1424. Fry ST. Ethical issues in Alzheimer disease research. Alzheimer Dis Assoc Disord 1999; 13 (Suppl 1): S54-S58. Kawas CH, Clark CM, Farlow MR, et al. Clinical trials in Alzheimer disease: debate on the use of placebo controls. Alzheimer Dis Assoc Disord 1999; 13: 124-129. Whitehouse PJ, Arizaga R, Brodaty H, et al. Placebos in clinical trials in Alzheimer disease: an international discussion. Alzheimer Dis Assoc Disord 1999; 13: 121-123. Make a comment

Robert D Goldney · Brian F Stoffell