SWORD trial of d-sotalol

THE LANCET

looking after our patient referrals, we pay the hospital a flat daily rate—a fraction of the rate charged at a typical American hospital. We now have contracts and agreements with ten hospitals in Croatia and Bosnia-Herzegovina. The project has been developed and implemented by young Croatian and Bosnian doctors and rehabilitation specialists on our staff. During this time of transition—when aid for emergency medical programmes in this region is diminishing, and development agencies have not yet implemented long-term medical projects—the challenge for medical professionals with an interest in former Yugoslavia is to find ways to help Croatian and Bosnian doctors care for their patients in this region. There are still a few Bosnian children who require surgery abroad. However, it should be mentioned that oncologists at the University Medical Centre in Sarajevo have been unable to obtain anti-neoplastic drugs for about 100 cancer patients for more than a year. Meeting such needs is beyond the resources of our project. Who will be these patients’ advocate? *Leila J Richards International Rescue Committee, HR-10 000 Z agreb, Croatia

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Southall D, Carballo M. Medical transfer programmes for Bosnia and Herzegovina. Lancet 1996; 347: 1838–39.

Occupational disease surveillance in Taiwan SIR—Exposure to workplace hazards causes or aggravates diseases as common and diverse as asthma, cancer, dermatitis, and tuberculosis.1 Work-related injuries apart, there were 30 837 occupational diseases from 1984 to 1990 in the UK, and crude estimates of incident cases range from 125 000 to 350 000 per year in the USA.2 In developing countries work-related diseases are seldom carefully enumerated. From 1987 to 1995, there were only 513 cases of occupational diseases entitled to insurance compensation in Taiwan. In a country with intensive industrial activity this figure must be a serious underestimate. Unfortunately, such shortage of information results in ignorance about the severity of occupational diseases among the public and policymakers. To overcome this shortage of information and to improve occupational medicine and industrial hygiene in Taiwan, the Ministry of Health set up a surveillance system in 1993. PRESS (Programme to Reduce Exposures by Surveillance System) has introduced three individual programmes—for monitoring blood lead (BLL),3 noise-induced hearing loss (NIHL), and work-related diseases (WORD). 4 With thorough communication with employees, employers, and local practitioners these programmes have now operated for 1 year since June, 1995. By May 31, 1996, 1374 suspected occupational cases have been reported to WORD, and 1076 (78·3%) have been confirmed by a committee composed of occupational medicine physicians and industrial hygienists. 15 527 audiograms of workers exposed to noisy working environments (>85 dBA) have been obtained by NIHL and 11 671 measurements of blood lead in lead-exposed workers have been reported to BLL. On the basis of our definitions (肁55 dB of hearing ability at 4 kHz or 肁40 µg/dL of blood lead in male workers and 肁30 µg/dL in females) 1270 cases of work-related hearing loss and 1074 cases of raised blood lead were found. The figures obtained via PRESS will not be the whole picture but there has been a substantial improvement in our understanding of the extent of severity of occupational

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diseases in Taiwan. Our experience with a surveillance system may serve as an example for other developing countries. *Trong-Neng Wu, Saou-Hsing Liou, Chen-Yang Shen, Chao-Chun Hsu, Show-Lin Chao, Po-Ya Chang Disease Surveillance and Quarantine Service, Ministry of Health, Taipei, Taiwan, ROC

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Cullen MR, Cherniack MG, Rosenstock L. Occupational medicine. N Engl J Med 1990; 322: 594–601, 675–83. Rosenstock L, Rest KM, Benson JA Jr, et al. Occupational and environmental medicine: meeting the growing need for clinical services. N Engl J Med 1991; 325: 924–27. Wu TN, Shen CY, Yang GY, et al. Establishment of an occupational diseases surveillance system to monitor blood lead levels in Taiwan. Prev Med 1995; 24: 85–88. Wu TN, Liou SH, Wang JD, et al. Establishment of a work-related diseases surveillance system in Taiwan, Republic of China. Prev Med (in press).

SWORD trial of d-sotalol SIR—Although the clear message from the SWORD investigators (July 6, p 7)1 is that pure potassium-channel blockers increase mortality in patients with ischaemic heart disease and impaired left ventricular systolic function, these researchers surprisingly presented no data to support the selection of such an alternative agent to be tested. In their introduction, they acknowledged that only ␤-adrenergic blockers and amiodarone might provide survival benefit, and they stated that the extrapolation that potassium-channel blockers other than amiodarone might be protective was unwarranted because of amiodarone’s various ion-channel and other effects. Furthermore, they mention the lack of beta-blocking activity of d-sotalol, and refer to only one experimental model in which the antifibrillatory activity of sotalol was documented. The SWORD investigators present no clinical evidence of the efficacy and safety of d-sotalol in the group of patients tested, and refer to only one experimental study on its potential usefulness. Could we ask them: why d-sotalol? Jalal K Ghali Louisiana State University Medical Center, Shreveport, LA 71130, USA

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Waldo AL, Camm AJ, deRuyter H, et al, for the SWORD investigators. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996; 348: 7–12.

SIR—Sanderson has rightly highlighted the dangers of proarrhythmic effects of antiarrhythmic agents (July 6, p 2)1 and suggested that there should be “a moratorium on antiarrhythmic drug trials until we can ensure the non-lethality of drugs before they are tried in patients”. This suggestion, however, invites the question: “How can we ensure nonlethality of drugs in patients?”. Detailed characterisation of the electrophysiological effects of antiarrhythmic drugs in isolated cardiac cells, tissues, or intact hearts have failed to predict which patient types will have increased propensity to the proarrhythmic effects of the drugs. Trials in animals, even in those with induced ischaemic heart disease, are fraught with difficulties, especially with the interpretation of their relevance to human patients. Clinical research in this area is handicapped by the fact that methods for detecting proarrhythmia are low in sensitivity and specificity. When dealing with patients, clinicians often find it difficult to be confident of stating whether the arrhythmia detected or provoked by

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electrophysiological testing or exercise is definitely lifethreatening, without being unduly alarmist. When no arrhythmia has been detected during multiple tests we also find it difficult to give categorical reassurance that the patient does not have life-threatening arrhythmia. Because of this, clinicians often feel obliged to consider antiarrhythmic therapy in patients with and without symptoms who are probably at risk of life-threatening arrhythmia. The CAST study2 provided the first concrete proof of the potential proarrhythmic harm of antiarrhythmic drugs. Following this, the licence for flecainide restricted its use only to treatment of life-threatening arrhythmia. If all other antiarrhythmic agents prescribable for non-life-threatening arrhythmia were put through the same protocol as flecainide in the CAST study, it is likely that several would also be found dangerous. We therefore arrive at a dilemma: although it may seem unethical to include patients in drug trials,1–3 such as CAST and SWORD (July 6, p 7),3 for fear of recording more deaths in the treatment arm, failure to conduct such studies would result in many patients being continually prescribed (for seemingly valid reasons) antiarrhythmic agents which may, because of their unspecified proarrhythmic potential, cause death. The latter mortality may be substantially greater than that which might be recorded in the trials. Equally worrying is Sanderson’s suggestion that only patients with symptomatic arrhythmia should be treated with antiarrhythmic agents. If strictly followed this could render some patients with symptomless but life-threatening arrhythmia unprotected. The alternative—the implantable defibrillator—is still prohibitively expensive for most patients. For the present, we have to accept that all drug trials can result in iatrogenic deaths. Obviously, safeguards must be incorporated in the trial designs to minimise mortality risk. In so identifying and characterising the harmful potential of drugs, clinicians can avoid the possibly greater and unquantifiable harm of uninformed prescribing. Decisions by ethics committees, for example, to prevent drug trials from proceeding may result in a greater general harm to patients. L B Tan Department of Cardiology, University of Leeds, Killingbeck Hospital, Leeds LS14 6UQ, UK

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Sanderson J. The SWORD of Damocles. Lancet 1996; 348: 2–3. Echt DS, Leibson PR, Mitchell LB, et al. The CAST Investigators. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781–88. Waldo AL, Camm AJ, deRuyter H, et al, for the SWORD investigators. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996; 348: 7–12.

activities, a major benefit was thought to be related to its blockade of potassium channels in cardiac cells. Consequently, research interest focused on the identification and development of less complex, better tolerated drugs with this specific activity. As we stated in our report, the SWORD trial tested the hypothesis that prolongation of action potential duration with a pure potassium-channel blocker could reduce all cause mortality in patients with previous myocardial infarction and ventricular dysfunction at increased risk of death. d-sotalol had substantial supportive preclinical and clinical experience as compared with similar compounds. Nearly 1000 patients had received the drug. Preliminary evidence showed antiarrhythmic efficacy with a low incidence of torsades de pointes, even in patients with life-threatening ventricular arrhythmias. Although we did not do a pilot study, we did do a run-in analysis on the first 500 patients, paying particular attention to the incidence of torsades de pointes and QT interval prolongation, and did not find any indication of adverse effects which would make us consider stopping the trial. This should not be a surprise because, on the basis of the Cardiac Arrhythmia Pilot Study,2 a small preliminary trial in postmyocardial infarction high-risk patients may not be useful in predicting efficacy or safety. Thus, the SWORD trial was a carefully planned, well executed, multinational study which was the largest of its kind. d-sotalol was an appropriate choice to explore an hypothesis that offered the promise of a new and important therapy. Although the results were not those that were anticipated, they were convincing. Once again we should recognise our limited knowledge of the mechanisms leading to sudden cardiac death, and the importance of double-blind, randomised, placebo-controlled, clinical trials testing the effect of antiarrhythmic therapy on all-cause mortality. We agree with Tan that there should not be a moratorium on antiarrhythmic drug trials. Our treatment decisions need to be based on objective medical evidence. In primary prevention trials of sudden death with prophylactic antiarrhythmic drug therapy, an appropriate risk/benefit assessment can best be achieved by use of randomised, placebo-controlled trials, such as SWORD, which enrol presumably high-risk patients under the supervision of a safety committee guided by prospectively defined stopping rules. Albert L Waldo, on behalf of the SWORD Investigators Division of Cardiology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA

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Authors’ reply SIR—Despite advances in treatment, survivors of a myocardial infarction with left ventricular dysfunction are at an increased risk for sudden cardiac death, for which there is limited effective therapy. When the SWORD trial was designed,1 the evidence indicated that sodium channel blocking antiarrhythmic drugs were harmful in these highrisk patients. β-adrenergic blocking drugs were helpful, but as documented in many studies, were used infrequently, perhaps because of impaired ventricular function. Drugs that prolong ventricular repolarisation (class III) were unproven, but preliminary evidence suggested potential benefit without apparent harm. Amiodarone was the prototype for this class, but it clearly had complex actions with difficult pharmacokinetics and important potential toxicity. Although the usefulness of amiodarone may be related to its multiple

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Waldo AL, Camm AJ, deRuyter H, et al. The SWORD trial: survival with oral d-sotalol in patients with left ventricular dysfunction after myocardial infarction: rationale, design and methods. Am J Cardiol 1995; 75: 1023–27. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: the CAPS. Am J Cardiol 1988; 61: 501–09.

Change in male:female ratio among newborn infants in Denmark SIR—It is well known that the human male:female ratio at birth has a slight male excess. Many factors have been identified that may affect the male:female ratio—eg, time of insemination within the cycle, birth order, age of the parents, and certain hormonal treatments and chemical exposures.1 James suggested2 that male reproductive hazards may usefully be monitored by low offspring male:female ratios, as an alternative to other indices such as sperm counts, conception waits, or hormone assays. There has

Vol 348 • September 21, 1996