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dilemmas. At the planned interim analysis, the local disease recurrence rates for the active treatment (intraarterial lipiodol-iodine-131) and control (no adjuvant treatment) groups were three/14 (21%) and 11/16 (69%) respectively (p=0·01). According to the predefined stopping rule, p<0·029 was sufficient for early stopping. The non-significant overall survival difference, three versus six deaths, was in the same direction. Thus, the investigators decided to stop the trial. Should the trial have been stopped when it was? There is a widely held view that very stringent p-values are required to stop a trial early on grounds of a treatment advance. Some investigators have argued for p<0·001 as a simple and effective guideline,5 using the phrase “proof beyond reasonable doubt” as the maxim that any DMC should adopt, but other slightly more complex sequences of increasing p-values have been proposed and used to good effect.6 In response to a US trial of extracorporeal membrane oxygenation in newborn infants that was stopped prematurely, Paul Meier referred to “a slightly hysterical view that we must stop as soon as we have an idea which treatment might be better”. 7 The stopping rule used by Lau and colleagues is commonly called a “Pocock boundary”, but Pocock does not advocate this cut-off for stopping a trial early because of benefit: pvalues near 0·05 are simply not persuasive enough to make a new treatment widely accepted.1 Estimating the potential magnitude of treatment benefit is important. However, both the observed benefit and the 95% CI are biased upwards when a trial is stopped early because the tendency is to stop a trial when by luck the observed treatment difference is on a “random high”, greater than the underlying truth. The consequence is that, as more data come in, either from the trial in question or a future trial, there is likely to be some “regression to the truth”—a diminution of the observed treatment difference. In the trial by Lau and colleagues, 13 more patients were randomised before the trial was stopped, and the investigators also decided to postpone analysis while patients already randomised were followed up. Hence, the report (18 months after the trial was stopped) reveals updated recurrence rates of six/21 (29%) and 13/22 (59%), respectively (p=0·04).Thus the absolute difference in recurrence rates shrank from 48% to 30% during the interval between stoppage and publication. Such “extra” data accumulated after a decision to stop can be informative, provided their selective timing is not influenced by how good or bad the results look. In this case, there were five extra recurrences (three on active and two on control treatment), and six extra deaths (one on active and five on control treatment). The extra recurrences are compatible with no true treatment benefit, whereas the extra deaths may be attributed to the previous difference in recurrences. Faced with a positive result for a small trial, one way of quantifying such potential shrinkage is to use Bayesian analysis, which combines a cautious distribution of prior belief with the limited but positive data to produce a potentially realistic posterior belief distribution.8 This is conceptually helpful but not often practicable, since a sensible prior belief has to be defined before the data arrive. A fundamental problem is that most cancer clinical trials are far too small.9 Even if the trial by Lau and 944

colleagues had reached its intended size of 120 patients, it would have lacked statistical power to detect realistic treatment benefits. It was designed to detect a halving of the recurrence rate with reasonable power, but surely a 25% reduction is still important to detect, and perhaps more likely to exist.This would require a trial size of 500 patients or more. Lau and colleagues’ trial exhibits some promising preliminary evidence for adjuvant intra-arterial lipiodoliodine-131 in hepatocellular carcinoma, but the verdict must remain open until further trial evidence is obtained. So why stop this trial? Our overall recommendation is that very convincing evidence of treatment benefit based on a large number of patients is required to stop and publish a clinical trial ahead of its preplanned completion. Stuar t Pocock, Ian White Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK 1 2

Pocock SJ. When to stop a clinical trial. BMJ 1992; 305: 235–40. Armstrong PW, Furberg CD. Clinical trial data and safety monitoring boards. Circulation 1995; 91: 901–04. 3 Fleming T, DeMets DL. Monitoring of clinical trials: issues and recommendations. Control Clin Trials 1993; 14: 183–97. 4 Lau WY, Leung TWT, Ho SKW, et al. Adjuvant intra-arterial iodine131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353: 797–801. 5 Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised controlled trials requiring prolonged observation of each patient. 1: introduction and design. Br J Cancer 1976; 34: 585–612. 6 DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 1994; 13: 1341–52. 7 Ware JH. Investigating therapies of potentially great benefit: ECMO (with discussion). Stat Sci 1989; 4: 298–340. 8 Pocock SJ, Hughes MD. Practical problems in interim analysis, with particular regard to estimation. Control Clin Trials 1989; 10: 209S–21S. 9 Freedman LS. The size of clinical trials in cancer research—what are the current needs? Br J Cancer 1989; 59: 396–400.

Cough and gastro-oesophageal reflux Cough is the commonest complaint for which patients seek medical attention,1 and it has a multiplicity of causes. In non-smoking patients who have a normal chest radiograph and are not on inhibitors of angiotensin-converting enzyme, the usual causes of chronic cough (greater than 3 weeks’ duration) are postnasal drip, bronchial asthma, and gastro-oesophageal reflux (GOR).1 In this subgroup, GOR, alone or in combination with another factor, is the cause of cough in 10–21% of adult patients.2,3 The primary event in GOR is the movement of acid and other gastric substances, including pepsin and bile salts, from the stomach into the oesophagus. In healthy individuals, reflux is a normal, asymptomatic event. Gastro-oesophageal reflux disease (GORD) is that which occurs when reflux leads to symptoms or physical complications. The majority of acid-reflux episodes are due to transient relaxation of the lower oesophageal sphincter (LOS) and not to reduced basal tone of the sphincter. In a prospective descriptive study (Evidence Grade II-3), Christopher Allen and Mehran Anvari4 found laparoscopic fundoplication to be effective in the management of cough in patients with proven GOR. Although the study group was heterogeneous, 62 of 195 patients did present primarily with respiratory symptoms, with chronic cough being the main complaint (68%). 16% had cough without heartburn or other typical GOR symptoms. All had not responded to omeprazole at doses of 40–80 mg daily. At 6 months after surgery, 83% of patients reported cure or

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improvement in their cough. These findings are consistent with other descriptive studies on reflux surgery.5,6 However, Allen and Anvari’s study raises some questions. First, what predisposes to cough in a patient with GORD? There was no significant difference between the group presenting with respiratory symptoms and the group presenting with predominantly gastrointestinal symptoms in 24 h oesophageal pH scores, LOS tone, or other reflux variables (before or after surgery ) .S e c o n d ,w hy was there no correlation between the severity of the cough and the severity of the reflux? Third, and perhaps most importantly, why, apart from a slightly lower LOS tone,

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was there no factor that could help differentiate responders from non-responders? There have been several investigations into the pathogenesis of cough associated with GOR. Possible mechanisms of cough include aspiration (macro and micro), heightened bronchial hyper-responsiveness, and vagally mediated distal oesophageal-tracheobronchial reflexes. In patients whose cough is unexplained after a systematic diagnostic assessment, including history and examination, chest radiography, laryngoscopy, paranasal sinus radiography, lung-function testing, bronchial provocation testing, and home peak-flow monitoring, cough is likely to be a result of stimulation by gastric acid of a distal oesophageal-tracheobronchial reflex mechanism, with no evidence of microaspiration or proximal oesophageal reflux.7,8 In such patients cough may be the sole presenting symptom of GOR,9 and there may be no macroscopic mucosal damage at oesophagoscopy. The initial investigation of choice in the assessment of GORD in this setting is therefore 24 h ambulatory oesophageal pH monitoring. In view of the frequency of GORD as a single or contributory cause of cough, and lack of facilities for 24 h pH monitoring in some places, empirical therapeutic trials are a common approach to the diagnosis of chronic cough. In chronic cough unexplained after a systematic diagnostic protocol, a trial of antireflux therapy is valid,1 even if there are no symptoms of GOR. However, if treatment fails, investigation of GORD (usually 24 h ambulatory oesophageal pH monitoring while the patient is on antireflux therapy) should be undertaken (figure). H2 antagonists have been the most widely studied antireflux dugs in patients with GORD and cough. When these drugs have been taken in conjunction with conservative and lifestyle measures, response rates of 80–84% for cough have been obtained. However, as in Allen and Anvari’s study, there is no correlation between severity of reflux and severity of cough, and no differences between responders and non-responders in pH profile, endoscopic appearances, or severity of cough. There has been no randomised controlled trial of proton-pump inhibitors in the treatment of cough associated with GORD. Theoretically, these agents may be more effective than H2 antagonists, and there has been anecdotal evidence of this effect.10 There is also good evidence to suggest that proton-pump inhibitors are significantly more effective than H2 antagonists in the treatment of asthmatic cough associated with GORD.11,12 Antireflux surgery is generally reserved for patients with proven GORD whose cough has not responded to medical therapy, including high doses of proton-pump inhibitors for at least 3 months. In four studies investigating the response of cough to antireflux therapy, only 0–4% of patients required antireflux surgery.3,9,13,14 The patients reported in Allen and Anvari’s study are therefore a very select group, with the cough failing to respond to omeprazole. Nevertheless, their reflux variables are no more severe than those in patients in other studies who have responded to H2 antagonists (9·4% of time spent at pH <4·0). Clearly then, severity of reflux does not predict response to treatment, nor does it predict the development of cough. However, oesophageal mucosal appearances were not used to grade severity. Of the three issues raised above by this study, the first two are unfortunately largely unanswered at present. If severity of GOR is not important in the pathogenesis of 945

cough, then what is? A distal oesophageal-tracheobronchial reflex is the commonest pathogenetic mechanism by which reflux triggers cough, yet it is manifested in only some patients with GORD. Oesophageal mucosal sensory receptor sensitisation, different response characteristics of oesophageal primary afferents, and a differential in the local release of protussive neurotransmitters in the tracheobronchial tree may all be important factors. However, these have not been investigated. Only recently have studies been undertaken to establish the anatomical existence and nature of the oesophageal-tracheobronchial reflex, as well as of the central “cough centre” which may also influence this reflex. The answer to the third question of what differentiates the responder from the non-responder is more easily addressed. In Allen and Anvari’s study, GOR was proven before surgery in all patients. Laparoscopic fundoplication resulted in an overall reduction in GOR symptoms, proportion of time spent at pH <4·0, and an increase in LOS tone. However, over 17% of patients still had persistent cough. The investigators correctly identify that cough may have multiple causes—several descriptive series have shown that multiple causes are present 18–62% of the time, and three disease processes may be responsible as much as 42% of the time.1 It is therefore important that chronic cough be assessed systematically, so that cough can be promptly diagnosed and treated, and so that unnecessary investigations and therapy can be avoided.The American College of Chest Physicians (ACCP) has recently published evidence-based guidelines for the evaluation of chronic cough in both immunocompetent and immunocompromised adults (figure).1 It would be an interesting exercise to analyse those patients whose cough responded to antireflux surgery, versus the non responders, based on the performance of the ACCP protocol. *Alvin J Ing, Meng C Ngu Depar tments of Thoracic Medicine and Gastroenterology, Concord Hopsital, Concord, NSW 2139, Australia 1 Managing cough as a defence mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians. Chest 1998; 114: 133S–81S. 2 Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic cough due to gastro-oesophageal reflux: clinical, diagnostic and pathogenetic aspects. Chest 1993; 104: 1511–17. 3 Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation and outcomes of specific therapy. Am Rev Respir Dis 1990; 141: 640–47. 4 Allen CJ, Anvari M. Gastro-oesophageal reflux related cough and its response to laparoscopic fundoplication. Thorax 1998; 53: 963–68. 5 DeMeester T R ,B o n avina L, Lascone C, Courtney JV, Skinner DB. Chronic respiratory symptoms and occult gastro-oesophageal reflux: a prospective clinical trial and results of surgical therapy. Ann Surg 1990; 211: 337–45. 6 Giudicelli R, Dupin B, Surpas P, et al. Gastroesophageal reflux and respiratory manifestations: diagnostic approach, therapeutic indications and results. Ann Chir 1990; 47: 552–54. 7 Ing AJ, Ngu MC, Breslin ABX. Pathogenesis of chronic persistent cough associated with gastro-oesophageal reflux. Am J Respir Crit Care Med 1994; 149: 160–67. 8. Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic cough due to gastro-oesophageal reflux: clinical, diagnostic and pathogenetic aspects. Chest 1993; 104: 1511–17. 9 Irwin RS, Zawacki JK, Curley FJ, French CL, Hoffman PJ. Chronic cough as the sole presenting manifestation of gastro-oesophageal reflux. Am Rev Respir Dis 1989; 140: 1294–300. 10 Waring JP, Lacayo L, Hunter J, Katz E, Suwak B. Chronic cough and hoarseness in patients with severe gastroesophageal reflux disease: diagnosis and response to therapy. Dig Dis Sci 1995; 40: 1093 11 Meier JH, McNally PR, Punja M, et al. Does omeprazole improve respiratory function in asthmatics with gastro-oesophageal reflux ? A double blind, placebo-controlled crossover study. Dig Dis Sci 1994; 39: 2127–33.

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12 Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100: 395–405. 13 Ing AJ, Ngu MC, Breslin ABX. A randomised double-blind trial of ranitidine in patients with chronic persistent cough associated with gastro-oesophageal reflux. Am Rev Respir Dis 1992: 145 (suppl): A11. 14 Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a history of excessive sputum production. Chest 1995; 108: 991–97

The real millennium bug See page 995 The launch in London on World TB Day (Mar 24) of the charity TB Alert—which aims to increase awareness of tuberculosis and to support operational research in the worst affected countries—is an indicator of the heightened attention being given to tuberculosis. The Lancet’s contribution to World TB Day is the series of essays in this week’s issue. We thank John Grange and Alimuddin Zumla for suggesting essay topics and for their piece. The series sets out to examine the threat posed by tuberculosis to global health, to focus attention on the most vulnerable, and to offer hope of a way forward. The way forward advocated by WHO is directly observed therapy short-course (DOTS), now implemented in about 100 countries. 500 000 infectious cases were treated under DOTS in 1996, compared with 250 000 in 1994. When fully implemented, DOTS can achieve wonders, as exemplified by the BRAC-run programme in Bangladesh described by Mushtaque Chowdhury. Yet only a third of those treated by the avowedly “women-focused” BRAC programme are women, and in 1996 only 16·5% of infectious tuberculosis cases in Bangladesh were detected under the DOTS strategy. Although these local difficulties can probably be overcome, Dye and colleagues have calculated that, even if targets for case detection and cure under DOTS are met by 2010, “three-quarters of the worldwide tuberculosis burden would not be averted in the next 23 years”.1 As Alexander Pym and Stewart Cole note, “acknowledgement of the limitations of DOTS would help generate the political will needed to swiftly develop a new generation of tuberculosis-control strategies”. The best tuberculosis-control strategy is undoubtedly elimination of poverty. However, debt-interest repayments mean that poor countries often give back to the west at least as much as they receive in aid. Chifumbe Chintu and Alwyn Mwinga from Zambia suggest debt cancellation to free resources for tuberculosis control. In neighbouring Tanzania, debt-servicing payments for 1997 were $275 million—ie, a third of the government budget, or nine times expenditure on primary health care (http://www. oxfam.org/advocacy/papers/tanzania.htm, accessed March 15). Yet Tanzania is not scheduled to receive debt relief under the International Monetary Fund and World Bank Heavily Indebted Poor Countries initiative until 2002. This initiative is intended to assist the 41 countries with the highest debt burden. Although the resources freed by debt relief cannot be guaranteed to go into health care, if the blight of tuberculosis is not to continue well into the next millennium, the sustained government commitment called for under DOTS must include a commitment from western governments to give developing countries a chance to help themselves. John McConnell The Lancet, London WC1B 3SL, UK 1

Dye C, Garnett GP, Sleeman K, Williams BG. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998; 352: 1886-91.

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