Smoking, Lung Function and the Prognosis of Abdominal Aortic Aneurysm

Eur J Vasc Endovasc Surg 19, 636–642 (2000) doi:10.1053/ejvs.2000.1066, available online at http://www.idealibrary.com on

Smoking, Lung Function and the Prognosis of Abdominal Aortic Aneurysm The UK Small Aneurysm Trial Participants∗† Background: the UK Small Aneurysm Trial was established to test the benefit of prophylactic elective surgery for small abdominal aortic aneurysms (4.0–5.5 cm in diameter) and identify prognostic risk factors, including smoking. Patients, methods and outcomes: one thousand and ninety patients (902 men and 188 women, mean age 69.3 years) were randomised to either early elective surgery or ultrasonography surveillance until the aneurysm diameter exceeded 5.5 cm, mean follow-up was 4.6 years. Baseline assessments included lung function tests and cotinine (a smoking marker). The principal outcome measures were all-cause mortality and aneurysm rupture. Results: during the course of the trial, aneurysm rupture was diagnosed in 25 patients and 309 patients died. Whereas self-reported smoking status was not significantly associated with survival, patients without any trace of plasma cotinine had a significantly improved long-term (6-year) survival, p=0.02. Current smokers had a lower FEV1 than past- and never-smokers. FEV1 was the most powerful predictor of long-term (6-year) survival, the crude death rates per 100 person-years were 9.1, 6.9 and 4.6 for those with FEV1 <1.9 l, 1.9–2.5 l and >2.5 l respectively, p=0.001. Moreover, the rupture rate was 1.9% per year for patients positive for plasma cotinine compared with 0.5% in those without trace of plasma cotinine, p=0.004. Conclusions: self-reported smoking status underestimates the effect of continued smoking on the prognosis of patients with small abdominal aortic aneurysm. Patients with high plasma cotinine concentrations (smokers) have an increased risk of aneurysm rupture and poorer long-term survival. Key Words: Aortic aneurysm; Smoking; Cotinine; Rupture; Mortality.

Introduction Abdominal aortic aneurysm (AAA) is a common condition, most often found in older men with a significant history of smoking. There has been considerable debate as to whether patients with small AAAs benefit from prophylactic elective surgical repair, since this procedure carries a significant mortality risk and the risk of rupture of small aneurysms is thought to be small.1 Two randomized trials were established, one in the U.K. and one in the U.S.A.2,3 Both these trials investigated whether a policy of early elective surgery provides a better management of small aneurysms (4.0–5.5 cm in diameter) than a policy of ultrasonographic surveillance, which carries an increased risk of death from aneurysm. The U.K. trial, with 1090 patients, reported in 1998. This trial showed that ultrasonographic surveillance was safe, the annual rupture rate being only 1% and that early elective ∗ Please address all correspondence to: J. T. Powell, Department of Vascular Surgery, Imperial College at Charing Cross, St. Dunstans Road, London W6 8RP, U.K. † The members of the Committee and Trial Participants are listed in the Appendix. 1078–5884/00/060636+07 $35.00/0  2000 Harcourt Publishers Ltd.

surgery was not associated with an improved longterm survival.4 After 6 years of follow-up the survival in the early elective surgery arm (563 patients) and the surveillance arm (527 patients) was 64%.4 The costs and quality of life in the two treatment arms of the UK Small Aneurysm Trial have also been compared.5 The American trial has not yet reported. With the principal results of the UK Small Aneurysm Trial having been reported, we now focus attention on other matters important to vascular surgeons. What are the important prognostic factors for survival in a patient with a small AAA? Which baseline factors indicate an increased risk of aneurysm rupture? Smoking is the strongest and most consistent risk factor for the development of abdominal aortic aneurysm.6–9 Smoking has also been indicated as a risk factor for aneurysm expansion10 and is associated with pulmonary dysfunction and disease. Lung function declines with age. In non-smokers the mean loss of FEV1 is about 30 ml/year compared to the much higher loss of lung function in smokers (FEV1 decline of 50 ml/year).11 Here we have investigated how smoking and lung function, measured as FEV1 and FVC, influence operative and late mortality and risk of aneurysm rupture for patients with small AAA. An

UK Small Aneurysm Trial Participants

Methods The methods have been described elsewhere.3,4 Briefly, patients (aged 60–76 years) were entered into either the UK Small Aneurysm Trial or the Small Aneurysm Study from 93 hospitals across Britain. Fit patients who consented to randomisation in the Trial had an abdominal aortic aneurysm (AAA) 4.0–5.5 cm in diameter. In total, 1090 patients were randomised in the 4-year period from September 1991: 527 of these were allocated to serial ultrasonographic surveillance and 563 to early elective surgery.4 Nearly all patients (93%) adhered to the allocated treatment according to protocol. Patients in the surveillance arm were followed up at 6-monthly intervals until the aneurysm reached 5 cm in diameter and 3-monthly thereafter. Surgical repair was recommended when the aneurysm diameter exceeded 5.5 cm, the aneurysm became tender or had symptoms attributed to it, or the growth rate exceeded 1 cm/year. By the end of the trial (30 June, 1998) 841 patients had undergone aneurysm repair, 520 in the surgical arm and 321 in the surveillance arm, the age–sex-adjusted 30-day mortality was 5.8% and 7.1% respectively. Baseline blood samples were analysed for haemoglobin, full blood count, electrolytes and creatinine, cholesterol and cotinine. Plasma cotinine was analysed by radioimmunoassay (EURO/DPC Ltd., Caernarfon, U.K.), coefficient of variation 7%. The physiological measurements, including aneurysm diameter and lung function with a portable spirometer (Micromedical, Rochester, U.K.) were performed by five specially trained trial coordinators. These co-ordinators met every 6 months to ensure uniformity and reproducibility of measurements. All patients were flagged at the Office of National Statistics to enable us to receive automatic notification of emigration, death, place of death, underlying cause of death and whether an autopsy was

100 Patients surviving (%)

earlier analysis of patients in the UK Small Aneurysm Trial has shown that poor lung function was associated with an increased length of hospital stay following elective surgical repair and hence costs of the procedure.5,12 Perhaps surprisingly, the self-reported smoking status of patients in the UK Small Aneurysm Trial had no effect on long-term survival.4 In this report, we have used plasma cotinine (the long-lived stable metabolite of nicotine) as an objective marker of smoking. This has allowed us to assess more accurately the effects of smoking to highlight poor prognosis of current smokers with respect to mortality and aneurysm rupture.

637

Never

90 80

Ex-smoker

70 Current 60 50 0

Number at risk Current 404 Ex-smoker 620 Never 64

2 4 Survival (years) 346 553 57

178 315 36

6

34 71 11

Fig. 1. Survival stratified by self-reported smoking status at randomisation. Kaplan–Meier estimates, log rank p=0.02.

performed. Aneurysm rupture was ascertained either from the death certificate or from imaging and operative details. The cause of death in 92 patients (29% of deaths) was determined after autopsy and a further 152 patients (49% of deaths) died in hospital. Data analysis Statistical analysis for all-cause mortality and aneurysm rupture was undertaken according to a predefined plan, based on the total pool of 1090 patients. Patients were censored at 30 June, 1998 (the end of the trial), or if death had occurred earlier. For analysis of aneurysm rupture patients were also censored at the time of aneurysm repair. We compared Kaplan–Meier survival curves for time since randomisation or from initial aortic diameter measurement to aneurysm rupture with a log-rank test. We used Cox’s proportional hazards regression to estimate hazard ratios for mortality (adjusted for age, sex, initial aneurysm diameter, mean ankle/brachial pressure index, FEV1 use of aspirin, source of referral and treatment group). Similarly, we used Cox’s proportional hazards regression to estimate hazard ratios for rupture and to adjust these for age, sex and initial aneurysm diameter. Results Long-term survival At randomisation 404 (37%) patients reported as current smokers, 620 (57%) as ex-smokers and 64 (6%) claimed that they had never smoked. Kaplan–Meier and univariate analyses suggested that current smokers had a worse survival than ex-smokers (Fig. Eur J Vasc Endovasc Surg Vol 19, June 2000

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Table 1. The effect of self-reported smoking status and plasma cotinine concentration on mortality. Factor

Number of deaths/ number of patients

Crude death rate (per 100 person-years)

Unadjusted hazard/ ratio (95% CI)

Adjusted hazard/ ratio (95% CI)

Adjusted p-value∗

Smoking status Current Ex-smoker Never

113/404 159/620 17/64

8.7 6.4 6.5

1.36 (1.08–1.71) 1.0 1.0 (0.61–1.65) p=0.03

1.26 (0.98–1.61) 1.0 1.09 (0.63–1.87)

0.21

Cotinine concentration (nmoles/l) None 2–767 768–11569

125/561 82/248 75/247

5.4 8.4 8.0

1.10 per 500 nmoles/l (1.04–1.16) p=0.002

1.08 per 500 nmoles/l (1.01–1.15)

0.02

∗ Adjusted for baseline factors, randomised treatment group, age, sex, initial aneurysm diameter, mean of left and right ABPI, FEV1 aspirin life, source of referral, regional centre and type of hospital (teaching or district).

100 Patients surviving (%)

Patients surviving (%)

100 90 None 80 1–767 768–11 569

70 60

90 2.6–4.4 l

80

1.9–2.5 l 70 0.3–1.8 l 60

50 4 2 Survival (years) Number at risk by cotinine concentration (nmol/l) None 561 509 299 2–767 248 222 120 768–11 569 247 214 107 0

6

68 28 20

Fig. 2. Survival stratified by plasma cotinine concentration. Five hundred and sixty-one patients had cotinine recorded as zero. The remaining patients were divided around the median positive cotinine concentration to form two equally sized groups. Kaplan– Meier estimates, log rank p=0.002.

1, Table 1). However, after adjustment for other prognostic baseline variables the effect of current smoking on survival was no longer significant (Table 1). Plasma cotinine measurements were available for 1056 (97%) patients. Cotinine was not detected in the plasma of 561 (53%) of patients, indicating that they were not current smokers. Plasma cotinine was measurable in 495 (47%) of these 1056 patients, to indicate current or very recent smoking: this inluded 103 of the patients reporting as ex-smokers and 9 patients who reportedly had never smoked. The apparently improved survival of patients with no detectable plasma cotinine is shown in Fig. 2. The significance of this finding remained after adjustment for other baseline prognostic variables, p=0.02 (Table 1). Baseline lung function measurements (FEV1 and FVC) were available for 1063 patients (98%) and stratified according to self-reported smoking status in Table Eur J Vasc Endovasc Surg Vol 19, June 2000

0

2 4 Survival (years) Number at risk by FEV1 (l) <1.9 377 321 161 1.9–2.5 373 334 180 >2.5 313 291 184

6

30 36 38

Fig. 3. Survival for patients stratified by FEV1 at randomisation. The patients have been divided into tertile groups. Kaplan–Meier estimates, log rank p=0.001.

2. The effect of FEV1 on survival is shown in Fig. 3 and in Table 1. After adjustment for baseline risk factors a very significant association between good lung function and survival remained, p=0.001 (Table 1). There was a similar relationship between high FVC and improved survival (data not shown). There also was a very significant correlation between plasma cotinine concentration and FEV1 recorded at baseline (Spearman’s p=0.0004).

Rupture rates according to baseline variables Among the 1090 randomised patients, there were 25 recorded abdominal aortic aneurysm ruptures. Only 15 of these ruptures occurred in patients where the last recorded aneurysm diameter was less than 5.5 cm. The remaining 10 ruptures occurred in patients where the aneurysm had enlarged to >5.5 cm and were await-

UK Small Aneurysm Trial Participants

639

Table 2. Self-reported smoking status, plasma cotinine concentration and lung function. Smoking status

Cotinine concentration median (range) nmoles/l

FEV1 (l) median (IQR)

FVC (l) median (IQR)

Current (n=404) Ex-smoker (n=620)

810 (2–11569) [14] 0 (0–4144) [16]

2.0 (1.5–2.5) [14] 2.3 (1.7–2.7) [11]

3.0 (2.4–3.5) [14] 3.2 (2.7–3.8) [11]

0 (0–1591) [4]

2.4 (1.7–2.7) [2]

3.1 (2.4–3.5) [2]

Never (n=64)

The number of missing values is shown in square brackets.

No plasma cotinine

Patients surviving without rupture (%)

100 90

Plasma cotinine positive

80 70 60 50 0

1

Number at risk No 561 333 cotinine Positive 495 290 cotinine

2

3 4 Survival (years)

5

6

245

188

107

48

12

221

153

86

43

13

Fig. 4. Survival without rupture for patients stratified by plasma cotinine concentration. Kaplan–Meier estimates, log rank p=0.004.

ing surgery (two), had become unfit for surgery (four), refused surgery (two) or the planned repair had not been completed because of other abdominal pathology. The overall rupture rate in trial patients was 1% per year. In eight patients the event was verified at surgical repair and 17 died without surgical repair (including 15 deaths in hospital) and the event was recorded on the death certificate (including 10 autopsies). Of these ruptures 14 (56%) occurred in self-reported current smokers, but the increased risk of this group was only of borderline significance. In contrast, there were only 6 ruptures in patients with no trace of plasma cotinine compared with 19 ruptures in those with measurable plasma cotinine, giving rupture rates of 0.5% per year and 1.9% per year respectively, log rank p=0.004 (Fig. 4). The increased risk for those positive for plasma cotinine remained after adjustment for age, sex and initial aneurysm diameter, adjusted hazard ratio 3.33 (95% CI 1.32–8.40), p=0.011.

Discussion Screening studies, in older men, have indicated that the prevalence of small abdominal aortic aneurysms is 3–5%. This underscores the importance of understanding the

natural history of this condition and finding the best management. The results of the UK Small Aneurysm Trial have suggested that for most patients with small aneurysms ultrasonographic surveillance is a safe, costeffective policy.4,5 The current findings indicate that, in such patients, objective markers of smoking (plasma cotinine) and poor lung function are strong predictors of all-cause mortality after 6 years. Plasma cotinine also was strongly associated with aneurysm rupture. Smoking status appeared to have been inaccurately reported by 10% of patients and has again proved unreliable as an indicator of smoking habit. This unreliability of patient-reported habit probably explains why self-reported smoking status was not associated with all-cause mortality.4 Plasma (or urinary) cotinine is a test which is not routinely available. Under these circumstances, lung function tests are likely to provide the most important prognostic indicator and guide to patient management. Our findings confirm that, in patients with abdominal aortic aneurysm, continued smoking shortens patient survival and increases the risk of aneurysm rupture. There are several previous examples to indicate that patients with vascular disease find it difficult to honestly report whether they continue to smoke. For instance, self-reported smoking status has no effect on the outcome of vein bypass surgery but the use of a very long-lived smoking marker, plasma thiocyanate, showed that graft occlusion was twice as common in smokers as in those who no longer smoked.13,14 Nicotine and its metabolites are more specific markers of smoking than thiocyanate. Nicotine has a short plasma half-life, but its principal metabolite, cotinine, has a plasma half-life of 16 h. Therefore plasma cotinine assesses current or very recent smoking. In the UK Small Aneurysm Trial at least 103 patients appear to have inaccurately reported themselves as ex-smokers and nine patients appear to have inaccurately reported themselves as never having smoked. Even this level of inaccurate reporting (10%) has a significant effect on the interpretation of results. Continued smoking, as indicated by plasma cotinine, was associated with poor survival prospects and increased risk of rupture for patients with small abdominal aortic aneurysms. These findings are Eur J Vasc Endovasc Surg Vol 19, June 2000

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compatible with our previous observation that small aneurysms grow faster in smokers (assessed by plasma cotinine concentration).10 This presents a dilemma. Since current smokers have an increased risk of aneurysm rupture, should they be offered prophylactic elective surgical repair of a small abdominal aortic aneurysm? The answer to this question is a firm ‘‘No’’. The risk of rupture is low (1.9% in current smokers) and these patients have worse lung function, which is associated with a substantial increase in mortality risk following elective surgery. Lung function declines with age. There is good evidence showing that the age-related decline in lung function is much faster in current smokers, but can be reduced by stopping smoking.11,15 Therefore, it is not surprising that, for patients with small abdominal aortic aneurysm, there is a strong correlation between lung function and both plasma cotinine and reported smoking status. Previously, poor lung function has been associated with accelerated aneurysm growth and aneurysm rupture.16–18 Poor lung function (low FEV1) also is associated significantly with an increased 30-day mortality following aneurysm repair, with mortality doubling for each 1 l reduction of FEV1.19 When surgery is performed in patients with poor lung function, the risk of postoperative chest infections is likely to increase and this could lead to the observed increase in length of hospital stay and hence increased costs.12 Abdominal aortic aneurysm is a smoking-related disorder. All our findings reinforce the need to counsel patients with small abdominal aortic aneurysms to stop smoking. For patients with larger, symptomatic or tender aneurysms a course of preoperative chest physiotherapy could improve postoperative outcome. A randomised trial of chest physiotherapy for patients undergoing major abdominal surgery already has shown the benefit of this approach.20 Cardiac assessment is commonplace before elective surgery for abdominal aortic aneurysm. Our findings reinforce the need for formal evaluation of lung function before selection for aneurysm repair and highlight the potential benefits of preoperative chest physiotherapy for patients with abdominal aortic aneurysm. Acknowledgements The UK Small Aneurysm Trial was supported by the Medical Research Council, the British Heart Foundation, the Camelia Botnar Foundation and the BUPA Foundation.

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References 1 Nevitt MP, Ballard DJ, Hallett JW. Prognosis of abdominal aortic aneurysms: a population based study. N Engl J Med 1989; 321: 1009–1014. 2 Lederle FA, Wilson SE, Johnson GR et al. Design of the abdominal aortic Aneurysm Detection and Management Study. J Vasc Surg 1994; 20: 647–650. 3 UK Small Aneurysm Trial Participants. The UK Small Aneurysm Trial: design, methods and progress. Eur J Vasc Endovasc Surg 1995; 9: 42–48. 4 UK Small Aneurysm Trial Participants. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998; 352: 1649–1655. 5 UK Small Aneurysm Trial Participants. Health service costs and quality of life for early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998; 352: 1656–1660. 6 Hammond EC, Garfinkel L. Coronary heart disease, stroke and abdominal aortic aneurysm. Arch Environ Health 1967; 19: 167–182. 7 Reed D, Reed C, Stemmermann, Hayashi T. Are aortic aneurysms caused by atherosclerosis? Circulation 1992; 85: 205–211. 8 Alcorn HG, Wolfson SK, Sutton-Tyrell K, Kuller LH, O’Leary D. Risk factors for abdominal aortic aneurysms in older adults enrolled in the Cardiovascular Health Study. Arterioscl Thromb Vasc Biol 1996; 16: 963–970. 9 Lederle FA, Johnsson GR, Wilson SE et al. Prevalence and associations of abdominal aortic aneurysm detected through screening. Ann Intern Med 1997; 126: 441–449. 10 MacSweeney STR, Ellis M, Worrell PC, Greenhalgh RM, Powell JT. Smoking and growth rate of small abdominal aortic aneurysms. Lancet 1994; 344: 651–652. 11 Fletcher CM, Peto R, Tinker C, Speizer FE. The Natural History of Chronic Bronchitis and Emphysema: an 8 Year Study of Working Men in London. Oxford: Oxford University Press, 1976. 12 UK Small Aneurysm Trial Participants. Length of hospital stay following elective abdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg 1998; 16: 185–191. 13 Wiseman S, Kenchington G, Dain R et al. Influence of smoking and plasma factors on patency of femoropopliteal vein grafts. Br Med J 1989; 299: 643–646. 14 McCollum CN, Alexander C, Kenchington G, Franks PJ, Greenhalgh RM. Antiplatelet drugs in femoropopliteal vein bypasses: A multicenter study. J Vasc Surg 1991; 13: 150–162. 15 Muers MF. Quitting smoking and lungs. Lancet 1999; 354: 177– 178. 16 Sterpetti AV, Schultz RD, Feldhaus RJ et al. Factors influencing enlargement rate of small abdominal aortic aneurysms. J Surg Res 1987; 43: 211–219. 17 Cronenwett JL, Murphy TF, Zelenock GB et al. Actuarial analysis of variables associated with rupture of small abdominal aortic aneurysms. Surgery 1985; 98: 472–483. 18 UK Small Aneurysm Trial Participants. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. Ann Surg 1999; 230: 289–297. 19 UK Small Aneurysm Trial Participants. Risk factors for post-operative mortality following elective surgical repair of abdominal aortic aneurysm: results from the UK Small Aneurysm Trial. Br J Surg (2000, in press). 20 Olsen FH, Hahn I, Nordgren S, Lonroth H, Lundholm K. Randomized controlled trial of prophylactic chest physiotherapy in major abdominal surgery. Br J Surg 1997; 84: 1535–1538. Accepted 29 December 1999

UK Small Aneurysm Trial Participants

Appendix UK Small Aneurysm Trial Steering Committee: Professor R. M. Greenhalgh (Chairman), Professor J. T. Powell (Imperial College at Charing Cross), Professor F. G. R. Fowkes, Dr J. F. Forbes, Professor C. V. Ruckley (University of Edinburgh). Monitoring Committee: Professor P. A. Poole-Wilson (Chair). Sir N. Browse, Professor C. J. Bulpitt, Professor K. Burnand, Dr E. C. Coles, Dr A. Fletcher.

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Princess Margaret Hospital: Mr D. Finch (6), Mr D. B. Hocken (2) Southampton General Hospital: Mr G. E. Morris (1), Mr C. P. Shearman (4) Southmead Hospital: Mr P. Lear (4) Torbay Hospital: Mr P. Lewis (5) Yeovil District General Hospital: Mr R. J. Clarke (5) Scotland & N.E. England Regional Trial Director: Professor C. V. Ruckley

Trial Participants (number of randomised patients recruited in brackets)

Edinburgh R.I.: Mr A. M. Jenkins (1), Professor C. V. Ruckley (28) Aberdeen R.I.: Mr G. G. Cooper (18), Mr J. Engeset (38), Mr R. Naylor (1) Ayr Hospital: Mr G. Stewart (16) Dryburn Hospital, Durham: Mr J. Cumming (10) Dumfries & Galloway Royal Infirmary: Mr J. McCormick (8) Dunfermline & West Fife Hospital: Miss A. Howd (9), Mr A. Turner (6) Falkirk & District Infirmary: Mr D. R. Harper (5), Mr R. C. Smith (6) Freeman Hospital: Mr J. Chamberlain (10), Mr A. G. Jones (12), Mr M. G. Wyatt (2) Gartnavel General Hospital: Mr A. J. McKay (13) Ninewells Hospital: Mr J. C. Forrester (3), Mr P. McCollum (30), Mr P. A. Stonebridge (3) Perth Royal Infirmary: Mr A. I. G. Davidson (2) Queen Elizabeth Hospital: Mr R. Baker (4) Royal Victoria Infirmary: Mr J. L. R. Forsythe (1), Mr D. Lambert (8) Royal Northern Infirmary: Mr J. L. Duncan (11)

S.W. England and South Wales

The Midlands

Regional Trial Director: Professor M. Horrocks

Regional Trial Director: Professor P. R. F. Bell

Royal United Hospital: Mr J. Budd (6), Professor M. Horrocks (23) Bristol Royal Infirmary: Mr R. N. Baird (12), Mr P. Lamont (10) Derriford Hospital: Mr D. C. Wilkins (6), Mr S. Ashley (3) Dorset County Hospital: Mr K. Flowerdew (9) Frenchay Hospital: Mr A. Baker (7) Gloucester Royal Infirmary: Mr J. Earnshaw (4), Mr B. Heather (3) Morriston Hospital: Mr C. Gibbons (14) Neville Hall Hospital: Mr R. L. Blackett (8) New Royal Bournemouth General Hospital: Mr S. D. Parvin (30) North Devon District General Hospital: Mr D. R. Harvey (1) Princes of Wales Hospital: Mr R. Hedges (1).

Leicester Royal Infirmary: Professor P. R. F. Bell (25), Mr D. Ratliff (1) Derbyshire Royal Infirmary: Mr K. G. Callum (16), Mr J. R. Nash (17) Glenfield General Hospital: Mr D. S. McPherson (7) Kettering & General District Hospital: Mr R. E. Jenner (4), Mr R. Stewart (5) Kidderminster General Hospital: Mr P. R. Armitstead (8) Leicester General Hospital: Mr W. W. Barrie (5) Northampton General Hospital: Mr D. B. Hamer (6), Mr S. Powis (5) Northern General Hospital: Mr L. D. Coen (2), Mr J. Michaels (4), Mr C. L. Welsh (3) Nottingham Queen’s Medical Centre: Mr B. R. Hopkinson (5), Mr P. W. Wenham (14) Royal Hallamshire Hospital: Mr J. Beard (25) Sandwell District General Hospital: Mr A. Auckland (3)

Trial Coordinators: Sue Blair, Rebecca Clark, Carol Devine, Karen Ferguson, Sheila Hearn, Eileen Kerracher, Sarah Logan, Anna McCabe, Razia Meer-Baloch, Michelle Mossa, Anna Rattray, Katie Wilson. Data Management: Louise Brown, Peter Franks. ECG Coding: Mrs N. Keen, Mrs C. Rose. Blood Analysis: R. Mir Hassaine.

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Worcester Royal Infirmary: Mr J. Black (7), Mr R. Downing (6) Worcester Royal Infirmary: Mr N. C. Hickey (3) London & S.E. England Regional Trial Director: Professor R. M. Greenhalgh Charing Cross Hospital: Mr A. H. Davies (2), Professor R. M. Greenhalgh (39), Mr D. Nott (5) Colchester General Hospital: Mr A. R. L. May (33) Epsom District Hospital: Mr R. McFarland (11) Guy’s Hospital: Mr P. Taylor (15) Hillingdon Hospital: Mr J. W. P. Bradley (3), Mr T. Paes (9) Ipswich Hospital: Mr A. E. P. Cameron (7) Joyce Green Hospital: Mr A. McIrvine (18) Lewisham Hospital: Mr D. Negus (4), Mr P. R. Taylor (10) Medway Hospital: Mr C. M. Butler (2), Mr R. W. Hoile (1) Newham General Hospital: Mr B. Pardy (11) Princess Alexandra Hospital: Miss J. Ackroyd (9) Royal Free Hospital: Mr G. Hamilton (4) Royal Hampshire County Hospital: Mr R. Lane (1) Royal Surrey County Hospital: Mr A. E. B. Giddings (21) St Georges’s Hospital: Mr J. Dormandy (5), Mr R. Taylor (9) St Peter’s Hospital: Mr M. Thomas (18) St Thomas’ Hospital: Mr K. J. Burnand (7) University College Hospital: Mr M. Adiseshiah (3) West Middlesex Hospital: Mr P. Pattison (1) West Norwich Hospital: Mr J. Clarke (8), Mr J. Colin (9) Wexham Park Hospital: Mr P. Rutter (4) Whipps Cross Hospital: Mr S. Brearley (14), Mr M. Pietroni (1)

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N. England and North Wales Regional Trial Director: Professor C. N. McCollum University Hospital South Manchester: Professor C. N. McCollum (12) Arrowe Park Hospital: Mr M. G. Greaney (2), Mr D. Reilly (7) Blackburn Royal Infirmary: Mr W. G. Paley (1) Blackpool, Victoria Hospital: Mr M. Lambert (16) Burnley General Hospital: Mr R. Hughes (16) Clatterbridge Hospital: Mr S. Blair (2) Cumberland Infirmary: Mr J. E. G. Shand (1) Grimsby District General Hospital: Mr L. A. Donaldson (1) Hull Royal Infirmary: Mr J. M. D. Galloway (2), Mr A. R. Wilkinson (21) Leeds District General Hospital: Mr M. Gough (16) Leigh Infirmary: Mr J. Mosley (1) Macclesfield General Hospital: Mr D. M. Matheson (19) Manchester Royal Infirmary: Mr M. Walker (4) Oldham Royal Hospital: Mr N. Hulton (4) Pontefract General Infirmary: Mr M. I. Aldoori (4), Mr C. K. Yeung (1) Royal Preston Hospital: Mr A. R. Hearn (6) Royal Lancaster Infirmary: Mr J. Kelly (18) Stafford General Hospital: Mr D. Durrans (2), Mr B. Gwynn (3) Stoke City General Hospital: Mr G. B. Hopkinson (13) Telford General Hospital: Mr R. G. M. Duffield (18) The Infirmary Rochdale: Mr I. G. Schraibman (3) York District Hospital: Mr R. Hall (3), Mr S. H. Leveson (4) Glan Clwyd Hospital, Rhyl: Mr J. Clark (3), Mr O. Klimach (23)