613
RELIEF FROM SYMPTOMS IN TREATMENTAND CONTROL GROUPS I
Symptoms were partly or completely relieved in three-quarters of the treatment group after 8 weeks and in only a fifth of controls (p < 0-05) (table); fewer patients than controls had no relief from symptoms (p < 0-05). 1 patient had generalised itching while taking musapep for 4 weeks. He had complete relief from symptoms of dyspepsia, and treatment was discontinued. We conclude that musapep is a safe and effective treatment of NUD, which should be substantiated by double-blind, placebocontrolled trials. We suggest that a therapeutic trial with this drug is justified on clinical grounds before expensive investigations, which are scarce in a developing country such as ours, are done. Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India
ANIL ARORA M. P. SHARMA
Nyren O, Adani HO, Gustavsson S, Loof L Excess sick listing in social and economic non-ulcer dyspepsia. J Clin Gastroenterol 1986; 8: 339-45. 2. Lagarde S, Spiro HM. Non ulcer dyspepsia. Clin Gastroenterol 1984; 13: 437-46. 3. Nyren O, Adami HO, Gustavsson S, Lingdran PG, Loof F, Nyberg A. The epigastric distress syndrome, a possible disease entity identified by history and endoscopy in patients with non ulcer dyspepsia. J Clin Gastroenterol 1987; 9: 303-09. 4. Nadkarni KM. Musa sapientum or M paradisiace Indian materia medica with Ayurvedic, Unani and home remedies, 3rd ed. Bombay: Popular Book Depot,
superinfection of the wrist. Pyrazinamide was stopped in December, 1987. At that time, symptoms had completely resolved, and the fistula had closed. Isoniazid and rifampicin were continued for a further 9 months. 1 year after completion of treatment, the patient had no functional sequelae of the hand. In-vitro testing of the mycobacterial strain showed resistance to isoniazid, rifampicin, pyrazinamide, and fluoroquinolones. A mycobacterial origin should be looked for in the presence of an indolent chronic granulomatous tenosynovitis. However, confirmation of diagnosis requires use of adequate media with sufficiently long culture time. M avium is an unusual cause of atypical mycobacterial tenosynovitis. The best antibiotic regimen for such infection is not known since in-vitro testing in broth is not predictive of intracellular antimicrobial activity and clinical response,t and most infections occur in immunosuppressed patients. It is noteworthy that in our patient tenosynovitis was cured by a regimen in which none of the antibiotics was thought to be active. The combination of drugs, with a possible role for pefloxacin, might have acted synergistically on infected macrophages.2 We believe a multiple combination should be used to treat atypical mycobacterial tenosynovitis. Department of Internal Medicine, Hôtel-Dieu, F-44035 Nantes Cédex, France. and Laboratory of Microbiology, Hôpital G and R Laennec, Nantes
F. RAFFI D. MOINARD H. B. DRUGEON
1.
1954: 822. R, Lewis DA, Nasser N. The
antiulcerogenic activity of unripe plantin banana (Musa species). Br J Pharmacol 1984; 82: 107-16. 6. Sanyal SK, Banerjee CR, Das PK. Studies on peptic ulceration, II: role of banana m resistant and prednisolone induced ulcer in albino rats. Arch Int Pharmacodyn 1985; 155: 244. 7. Tripathy BM, Misra NP. Double blind randomized study of indegenous compound (banana powder) in management of peptic ulcer. J Assoc Physicians India 1986; 34:
Yajko DM, Nassos PS, Sanders CA, Hadley WK. Killing by antimycobacterial agents of AIDS-derived strains of Mycobacterium avium complex inside cells of the mouse macrophage cell line J774. Am Rev Respir Dis 1989; 140: 1198-203. 2. Carlone NA, Acocella G, Cuffini AM, Forno-Pizzoglio M. Killing of macrophageingested mycobacteria in rifampicin, pyrazinamide and pyrazinoic acid alone and in combination. Am Rev Respir Dis 1985; 132: 1274-77. 1.
5 Best
58.
Non-tuberculous mycobacterial
tenosynovitis SiR,—Dr Colville and Dr Ispahani (Nov 11, p 1161) note the importance of clinical suspicion of atypical mycobacterial origin in tenosynovitis. Delayed diagnosis might be harmful and antibiotic treatment could be curative, even for long-standing lesions. We report a patient in whom the diagnosis of mycobacterial tenosynovitis was delayed for over 4 years. A 46-year-old farmer was seen in August, 1987, for persistent swelling of the anterior side of the right wrist. This swelling was first noticed in March, 1983, and synovectomy was done in August, 1984. Histology had shown granulomatous lesions. Cultures remained sterile, but media specific for mycobacteria were not used. The Mantoux test was negative and no specific treatment was given. In June, 1987, swelling and pain in the right wrist were again noted, and in July, 1987, the right hand was found to be painful and oedematous, with a swollen, indurated, discharging lesion of the wrist. Tenosynovectomy was done under general anaesthesia. Flexor tendons were inflamed and surrounded by necrotic and friable tissue. Histology showed histiocytic and giant cell granulomata. Acid-fast bacilli were not looked for. Swelling and suppuration persisted after operation and the patient was readmitted in August, 1987. He was generally well and afebrile, with a swollen, non-inflamed discharging wrist. Flexion of the last two fingers of the right hand was almost impossible. No other abnormalities were noted. Serous fluid discharging from the wrist was aspirated on three consecutive days. No acid-fast bacilli were found, and cultures on standard media were sterile. Treatment with rifampicin, isoniazid, and pyrazinamide was started. Cultures grew Mycobacterium avium after 2 months. Pefloxacin (800 mg daily for 3 months) was added in October, 1987, because of Serratia
Anti-phospholipid antibodies and ischaemic optic neuropathy SIR,-The aetiology of giant-cell arteritis is unknown. Various mechanisms have been suggested, including an immunological pathogenesis.’ The recognition of a strong association between antiphospholipid antibodies (APA) and thrombosis has identified a new component in several vascular events, such as arterial and venous thromboses.2 Thus APA could have a role in the pathogenesis of vascular occlusion in giant-cell arteritis. Ten consecutive patients presenting with acute ischaemic optic neuropathy were studied. In five this was of a "non-arteritic" form (sudden painless visual loss, pallid oedema of the optic disc, and a negative temporal artery biopsy) and in the other five it was secondary to previously undiagnosed giant-cell arteritis, confirmed by biopsy. One patient had a history of deep venous thrombosis and one had had a cerebrovascular accident but there was no other history of thrombotic events. One patient had been using a phenothiazine, which can induce a lupus-like anticoagulant. Investigations included ophthalmological examination, temporal artery biopsy, and coagulation tests for lupus anticoagulant (DRVVT with platelet neutralisation procedure and KCCT); IgG and IgM antibodies to cardiolipin were sought by ELISA. Because of the skewed distribution the upper limit of normal was defined as mean + 3 SD for seventy healthy controls. In all the patients with giant cell arteritis, the IgG anticardiolipin (ACA) level was raised (table). In the non-arteritic group anticardiolipin levels were not increased. ACA belong to a family of anti-phospholipid antibodies that includes lupus anticoagulant and the false-positive test for syphilis. The coagulation tests used excluded the presence of lupus anticoagulant. The presence of ACA in the serum of all five patients with giant-cell arteritis, in the absence of any abnormality of coagulation, suggests an association with antibodies differing in specificity from those seen, for example, in systemic lupus erythematosus, when all three types of antiphospholipid antibody are often found. Whether this association between giant-cell arteritis and ACA is causal or an effect of the disease is not clear, but the lack of systemic symptoms and the normal or slightly raised
614
CLINICAL AND IMMUNOLOGICAL DATA
*Systemic features, tHistory of vascular events
rates, together with the absence of antibodies in the five without arteritis, does argue for a pathogenic role, and suggests a rationale for the use of immunosuppressive therapy. ACA should be sought in patients with ischaemic optic
erythrocyte sedimentation
neuropathy.
Royal Hallamshire Hospital, Sheffield S10 2JF, UK
M. T. WATTS M. GREAVES L. G. CLEARKIN R. G. MALIA S. M. COOPER
1. Anderson
R, Hansson GK, Soderstrom T, Jonsson R, Bengtsson BA, Nordberg E. HLA-DR expression in the vascular lesion and circulating T-lymphocytes of patients with giant cell arteritis. Clin Exp Immunol 1988; 73: 82-87. 2. Harris EN, Asherson RA, Hughes GRV. Antiphospholipid antibodies_ autoantibodies with a difference. Annu Rev Med 1988; 39: 261-71. 3. Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the anticardiolipin antibody test: report of an international workshop held on 4th April 1986. Clin Exp Immunol 1987; 68: 215-19.
Statistics in clinical trials SIR,-Mr Altman and Ms Dore (Jan 20, p 149) note the failure of others to explain sample size, yet they do not explain the sample size in their own study. Was their choice of 80 trials based on statistical power, the time period of the journals scanned, or the work load involved in detailed analysis of the papers? Before starting their study, Altman and Dore might have calculated that with a sign test, 80 trials, and a two-tailed p of 0-05, the statistical power is 80% (which is acceptable) for a medium-sized difference between groups, but only 16% for a small difference.The hypothesis testing that they did is on subgroups, the biggest n being 36. Here, for the sign test, power is 49% and 11% for a medium and a small difference, respectively. In case your contributors were "selling themselves short" by under-reporting procedures rather than failing to do them, I did consider telephoning’ them, but decided instead to keep tongue firmly in cheek. After all, too much detail can clutter an article and Lancet readers appreciate brevity in authors, including Altman and
Dore.
intention to treat was done in less than 20% of trials. To avoid bias in overviews it is necessary to include wellrandomised trials and intention-to-treat analysis.2 A checklist may improve the quality of reports but more needs to be done to improve the quality of the trials themselves. Doctors and students should be taught more about RCTs. Department of Medical Statistics, Institut Gustave Roussy, 94805 Villejuif, France
MORRIS BERNADT
J. Statistical power analysis for the behavioural sciences. New York and London: Academic Press, 1969: 155-56. 2. Liberati A, Himel HN, Chalmers TC. A quality assessment of randomised controlled trials of primary treatment of breast cancer. J Clin Oncol 1986; 4: 942-51. 1. Cohen
SIR,-Mr Altman and Ms Dore’s review of randomisation and baseline data in randomised clinical trials (RCT), because it was limited to four leading general medical journals, gives us an optimistic view of methodological quality. In an overview of studies on healing in duodenal ulcer we looked at 293 RCTs published between 1976 and 1987 as full papers or
J. P. PIGNON
Gastroenterology Service, Hôpital Antoine Béclère, Clamart
T. POYNARD
1.
Poynard T, Pignon JP. Acute treatment of duodenal ulcer: analysis of 293 randomized clinical trials. Montrouge: John Libbey Eurotext, 1989. 2. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overview. Stat Med 1987; 6: 245-50.
SiR,—Overall, randomisation to groups in a controlled trial is balanced; for a given allocation it is not. Whether we take comfort from the first fact or take fright at the second, a significance test on Thus far I agree with Mr Altman and Ms Dore’s discussion of baseline comparability. If, however, it were appropriate to look at baseline comparability to decide what statistical analysis to do, the decision would depend on the correlation between baseline and outcome variable and on the standardised between-group difference2,3-not, as Altman and Dore claim, on absolute differences in means or proportions. However, examination for this purpose is not logical. For normally distributed outcomes the logical strategy is to select a set of prognostic variables before randomisation and to use these in an analysis of covariance whatever the imbalance.3Corresponding methods are available for other types of data. Using change from baseline is not, as Altman and Dore claim, an adequate method for dealing with baseline imbalance; if the correlation coefficient between outcome and baseline is less than 05 it is worse than just using the raw outcome measures.,,4 Looking at prognostic covariates, whether formally in terms of significance tests or by "subjective substantial difference in means or proportions" is no substitute for using them.
prognostic factors is irrelevant.’
Medical Department,
Ciba-Geigy Ltd, 4002 Basle, Switzerland
Department of Psychological Medicine, King’s College Hospital, London SE5 9RS, UK
proceedings in English, French, Italian, Portuguese, or Spanish.’ Methodological quality was assessed independently by each of us on a 14-item score ranging from 0 to 28. Disagreements were resolved by discussion. The trials were divided by year of publication into three groups: 1976-80 (n = 87), 1981-84 (n =116), and 1985-87 (n = 87). The method of generating random numbers and the mechanism used to allocate treatment were reported in only 3% of the trials; 25% of trials described one or other method. Details of randomisation did not improve with time despite a significant improvement in mean quality score from 14 to 16. Data on sample size calculation (0%, 3%, and 17% in the three consecutive periods) and adequate covariable analysis (30%, 47%, and 74%) improved significantly with time. 87% of RCTs reported the proportion of patients withdrawn but even in the latest period analysis by
STEPHEN SENN
1. Senn SJ. The use of baselines m clinical trials of bronchodilators. Stat Med 1989; 8: 1339-50. 2. Lewis J. Clinical trials: statistical developments of practical benefit to the pharmaceutical industry. J R Statist Soc A 1983; 146: 362-93. 3. Senn SJ. Covariate imbalance and random allocation in clinical trials. Stat Med 1989; 8: 467-75. 4. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7-20.
CORRECTION Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin.-In this article by Dr 1. Macdougall and others (March 3, p 489) the 4th sentence of the summary should read: "Carbon monoxide transfer rose from 15-5 (2-9) to 18-6 (3-7) ml. min-’. mm Hg-l."
RELIEF FROM SYMPTOMS IN TREATMENTAND CONTROL GROUPS I
Symptoms were partly or completely relieved in three-quarters of the treatment group after 8 weeks and in only a fifth of controls (p < 0-05) (table); fewer patients than controls had no relief from symptoms (p < 0-05). 1 patient had generalised itching while taking musapep for 4 weeks. He had complete relief from symptoms of dyspepsia, and treatment was discontinued. We conclude that musapep is a safe and effective treatment of NUD, which should be substantiated by double-blind, placebocontrolled trials. We suggest that a therapeutic trial with this drug is justified on clinical grounds before expensive investigations, which are scarce in a developing country such as ours, are done. Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India
ANIL ARORA M. P. SHARMA
Nyren O, Adani HO, Gustavsson S, Loof L Excess sick listing in social and economic non-ulcer dyspepsia. J Clin Gastroenterol 1986; 8: 339-45. 2. Lagarde S, Spiro HM. Non ulcer dyspepsia. Clin Gastroenterol 1984; 13: 437-46. 3. Nyren O, Adami HO, Gustavsson S, Lingdran PG, Loof F, Nyberg A. The epigastric distress syndrome, a possible disease entity identified by history and endoscopy in patients with non ulcer dyspepsia. J Clin Gastroenterol 1987; 9: 303-09. 4. Nadkarni KM. Musa sapientum or M paradisiace Indian materia medica with Ayurvedic, Unani and home remedies, 3rd ed. Bombay: Popular Book Depot,
superinfection of the wrist. Pyrazinamide was stopped in December, 1987. At that time, symptoms had completely resolved, and the fistula had closed. Isoniazid and rifampicin were continued for a further 9 months. 1 year after completion of treatment, the patient had no functional sequelae of the hand. In-vitro testing of the mycobacterial strain showed resistance to isoniazid, rifampicin, pyrazinamide, and fluoroquinolones. A mycobacterial origin should be looked for in the presence of an indolent chronic granulomatous tenosynovitis. However, confirmation of diagnosis requires use of adequate media with sufficiently long culture time. M avium is an unusual cause of atypical mycobacterial tenosynovitis. The best antibiotic regimen for such infection is not known since in-vitro testing in broth is not predictive of intracellular antimicrobial activity and clinical response,t and most infections occur in immunosuppressed patients. It is noteworthy that in our patient tenosynovitis was cured by a regimen in which none of the antibiotics was thought to be active. The combination of drugs, with a possible role for pefloxacin, might have acted synergistically on infected macrophages.2 We believe a multiple combination should be used to treat atypical mycobacterial tenosynovitis. Department of Internal Medicine, Hôtel-Dieu, F-44035 Nantes Cédex, France. and Laboratory of Microbiology, Hôpital G and R Laennec, Nantes
F. RAFFI D. MOINARD H. B. DRUGEON
1.
1954: 822. R, Lewis DA, Nasser N. The
antiulcerogenic activity of unripe plantin banana (Musa species). Br J Pharmacol 1984; 82: 107-16. 6. Sanyal SK, Banerjee CR, Das PK. Studies on peptic ulceration, II: role of banana m resistant and prednisolone induced ulcer in albino rats. Arch Int Pharmacodyn 1985; 155: 244. 7. Tripathy BM, Misra NP. Double blind randomized study of indegenous compound (banana powder) in management of peptic ulcer. J Assoc Physicians India 1986; 34:
Yajko DM, Nassos PS, Sanders CA, Hadley WK. Killing by antimycobacterial agents of AIDS-derived strains of Mycobacterium avium complex inside cells of the mouse macrophage cell line J774. Am Rev Respir Dis 1989; 140: 1198-203. 2. Carlone NA, Acocella G, Cuffini AM, Forno-Pizzoglio M. Killing of macrophageingested mycobacteria in rifampicin, pyrazinamide and pyrazinoic acid alone and in combination. Am Rev Respir Dis 1985; 132: 1274-77. 1.
5 Best
58.
Non-tuberculous mycobacterial
tenosynovitis SiR,—Dr Colville and Dr Ispahani (Nov 11, p 1161) note the importance of clinical suspicion of atypical mycobacterial origin in tenosynovitis. Delayed diagnosis might be harmful and antibiotic treatment could be curative, even for long-standing lesions. We report a patient in whom the diagnosis of mycobacterial tenosynovitis was delayed for over 4 years. A 46-year-old farmer was seen in August, 1987, for persistent swelling of the anterior side of the right wrist. This swelling was first noticed in March, 1983, and synovectomy was done in August, 1984. Histology had shown granulomatous lesions. Cultures remained sterile, but media specific for mycobacteria were not used. The Mantoux test was negative and no specific treatment was given. In June, 1987, swelling and pain in the right wrist were again noted, and in July, 1987, the right hand was found to be painful and oedematous, with a swollen, indurated, discharging lesion of the wrist. Tenosynovectomy was done under general anaesthesia. Flexor tendons were inflamed and surrounded by necrotic and friable tissue. Histology showed histiocytic and giant cell granulomata. Acid-fast bacilli were not looked for. Swelling and suppuration persisted after operation and the patient was readmitted in August, 1987. He was generally well and afebrile, with a swollen, non-inflamed discharging wrist. Flexion of the last two fingers of the right hand was almost impossible. No other abnormalities were noted. Serous fluid discharging from the wrist was aspirated on three consecutive days. No acid-fast bacilli were found, and cultures on standard media were sterile. Treatment with rifampicin, isoniazid, and pyrazinamide was started. Cultures grew Mycobacterium avium after 2 months. Pefloxacin (800 mg daily for 3 months) was added in October, 1987, because of Serratia
Anti-phospholipid antibodies and ischaemic optic neuropathy SIR,-The aetiology of giant-cell arteritis is unknown. Various mechanisms have been suggested, including an immunological pathogenesis.’ The recognition of a strong association between antiphospholipid antibodies (APA) and thrombosis has identified a new component in several vascular events, such as arterial and venous thromboses.2 Thus APA could have a role in the pathogenesis of vascular occlusion in giant-cell arteritis. Ten consecutive patients presenting with acute ischaemic optic neuropathy were studied. In five this was of a "non-arteritic" form (sudden painless visual loss, pallid oedema of the optic disc, and a negative temporal artery biopsy) and in the other five it was secondary to previously undiagnosed giant-cell arteritis, confirmed by biopsy. One patient had a history of deep venous thrombosis and one had had a cerebrovascular accident but there was no other history of thrombotic events. One patient had been using a phenothiazine, which can induce a lupus-like anticoagulant. Investigations included ophthalmological examination, temporal artery biopsy, and coagulation tests for lupus anticoagulant (DRVVT with platelet neutralisation procedure and KCCT); IgG and IgM antibodies to cardiolipin were sought by ELISA. Because of the skewed distribution the upper limit of normal was defined as mean + 3 SD for seventy healthy controls. In all the patients with giant cell arteritis, the IgG anticardiolipin (ACA) level was raised (table). In the non-arteritic group anticardiolipin levels were not increased. ACA belong to a family of anti-phospholipid antibodies that includes lupus anticoagulant and the false-positive test for syphilis. The coagulation tests used excluded the presence of lupus anticoagulant. The presence of ACA in the serum of all five patients with giant-cell arteritis, in the absence of any abnormality of coagulation, suggests an association with antibodies differing in specificity from those seen, for example, in systemic lupus erythematosus, when all three types of antiphospholipid antibody are often found. Whether this association between giant-cell arteritis and ACA is causal or an effect of the disease is not clear, but the lack of systemic symptoms and the normal or slightly raised
614
CLINICAL AND IMMUNOLOGICAL DATA
*Systemic features, tHistory of vascular events
rates, together with the absence of antibodies in the five without arteritis, does argue for a pathogenic role, and suggests a rationale for the use of immunosuppressive therapy. ACA should be sought in patients with ischaemic optic
erythrocyte sedimentation
neuropathy.
Royal Hallamshire Hospital, Sheffield S10 2JF, UK
M. T. WATTS M. GREAVES L. G. CLEARKIN R. G. MALIA S. M. COOPER
1. Anderson
R, Hansson GK, Soderstrom T, Jonsson R, Bengtsson BA, Nordberg E. HLA-DR expression in the vascular lesion and circulating T-lymphocytes of patients with giant cell arteritis. Clin Exp Immunol 1988; 73: 82-87. 2. Harris EN, Asherson RA, Hughes GRV. Antiphospholipid antibodies_ autoantibodies with a difference. Annu Rev Med 1988; 39: 261-71. 3. Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the anticardiolipin antibody test: report of an international workshop held on 4th April 1986. Clin Exp Immunol 1987; 68: 215-19.
Statistics in clinical trials SIR,-Mr Altman and Ms Dore (Jan 20, p 149) note the failure of others to explain sample size, yet they do not explain the sample size in their own study. Was their choice of 80 trials based on statistical power, the time period of the journals scanned, or the work load involved in detailed analysis of the papers? Before starting their study, Altman and Dore might have calculated that with a sign test, 80 trials, and a two-tailed p of 0-05, the statistical power is 80% (which is acceptable) for a medium-sized difference between groups, but only 16% for a small difference.The hypothesis testing that they did is on subgroups, the biggest n being 36. Here, for the sign test, power is 49% and 11% for a medium and a small difference, respectively. In case your contributors were "selling themselves short" by under-reporting procedures rather than failing to do them, I did consider telephoning’ them, but decided instead to keep tongue firmly in cheek. After all, too much detail can clutter an article and Lancet readers appreciate brevity in authors, including Altman and
Dore.
intention to treat was done in less than 20% of trials. To avoid bias in overviews it is necessary to include wellrandomised trials and intention-to-treat analysis.2 A checklist may improve the quality of reports but more needs to be done to improve the quality of the trials themselves. Doctors and students should be taught more about RCTs. Department of Medical Statistics, Institut Gustave Roussy, 94805 Villejuif, France
MORRIS BERNADT
J. Statistical power analysis for the behavioural sciences. New York and London: Academic Press, 1969: 155-56. 2. Liberati A, Himel HN, Chalmers TC. A quality assessment of randomised controlled trials of primary treatment of breast cancer. J Clin Oncol 1986; 4: 942-51. 1. Cohen
SIR,-Mr Altman and Ms Dore’s review of randomisation and baseline data in randomised clinical trials (RCT), because it was limited to four leading general medical journals, gives us an optimistic view of methodological quality. In an overview of studies on healing in duodenal ulcer we looked at 293 RCTs published between 1976 and 1987 as full papers or
J. P. PIGNON
Gastroenterology Service, Hôpital Antoine Béclère, Clamart
T. POYNARD
1.
Poynard T, Pignon JP. Acute treatment of duodenal ulcer: analysis of 293 randomized clinical trials. Montrouge: John Libbey Eurotext, 1989. 2. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overview. Stat Med 1987; 6: 245-50.
SiR,—Overall, randomisation to groups in a controlled trial is balanced; for a given allocation it is not. Whether we take comfort from the first fact or take fright at the second, a significance test on Thus far I agree with Mr Altman and Ms Dore’s discussion of baseline comparability. If, however, it were appropriate to look at baseline comparability to decide what statistical analysis to do, the decision would depend on the correlation between baseline and outcome variable and on the standardised between-group difference2,3-not, as Altman and Dore claim, on absolute differences in means or proportions. However, examination for this purpose is not logical. For normally distributed outcomes the logical strategy is to select a set of prognostic variables before randomisation and to use these in an analysis of covariance whatever the imbalance.3Corresponding methods are available for other types of data. Using change from baseline is not, as Altman and Dore claim, an adequate method for dealing with baseline imbalance; if the correlation coefficient between outcome and baseline is less than 05 it is worse than just using the raw outcome measures.,,4 Looking at prognostic covariates, whether formally in terms of significance tests or by "subjective substantial difference in means or proportions" is no substitute for using them.
prognostic factors is irrelevant.’
Medical Department,
Ciba-Geigy Ltd, 4002 Basle, Switzerland
Department of Psychological Medicine, King’s College Hospital, London SE5 9RS, UK
proceedings in English, French, Italian, Portuguese, or Spanish.’ Methodological quality was assessed independently by each of us on a 14-item score ranging from 0 to 28. Disagreements were resolved by discussion. The trials were divided by year of publication into three groups: 1976-80 (n = 87), 1981-84 (n =116), and 1985-87 (n = 87). The method of generating random numbers and the mechanism used to allocate treatment were reported in only 3% of the trials; 25% of trials described one or other method. Details of randomisation did not improve with time despite a significant improvement in mean quality score from 14 to 16. Data on sample size calculation (0%, 3%, and 17% in the three consecutive periods) and adequate covariable analysis (30%, 47%, and 74%) improved significantly with time. 87% of RCTs reported the proportion of patients withdrawn but even in the latest period analysis by
STEPHEN SENN
1. Senn SJ. The use of baselines m clinical trials of bronchodilators. Stat Med 1989; 8: 1339-50. 2. Lewis J. Clinical trials: statistical developments of practical benefit to the pharmaceutical industry. J R Statist Soc A 1983; 146: 362-93. 3. Senn SJ. Covariate imbalance and random allocation in clinical trials. Stat Med 1989; 8: 467-75. 4. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7-20.
CORRECTION Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin.-In this article by Dr 1. Macdougall and others (March 3, p 489) the 4th sentence of the summary should read: "Carbon monoxide transfer rose from 15-5 (2-9) to 18-6 (3-7) ml. min-’. mm Hg-l."
