- Email: [email protected]
Atrial fibrillation control and cardioversion
CORRESPONDENCE
2
3
4
Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask. JAMA 2000; 284: 2352–60. Rusterholtz T, Kempf J, Berton C, et al. Noninvasive pressure support ventilation (NIPSV) with face mask in patients with acute pulmonary edema (ACPE). Intensive Care Med 1999; 25: 21–28. Carbone G, Di Battista N, Nava S, Noninvasive bilevel ventilation vs conventional therapy in the treatment of acute cardiogenic pulmonary oedema: a randomised study. Eur Respir J 2000; 16: A3815.
Management of peanut and nut allergy Sir—David Hill and colleagues in their Jan 13 Commentary1 feel it premature to adopt our management plan for nut allergy,2 but they have missed the point. The evidence they quote from other studies: that, in patients with peanut and nut allergy, further reactions occur in 50–58% and that mild-index reactions are followed by severe reactions in 38–44%, surely underline the effectiveness of our treatment plan. In our study, only 15% of patients had further reactions, most of which were mild. This finding suggests that the avoidance arm of our protocol was effective. Hill and colleagues focus on drug treatment of reactions only, whereas we advocate an overall strategy including prevention of further reactions. Hill and colleagues are concerned that the outcome may have been favourably affected by resolution of the allergy (a factor we discussed) or incorrect diagnosis, but these factors would also apply to the other series. They wonder whether our results were influenced by the 154 patients not followed up: 62% had not reached their first follow-up appointment so no data had been obtained; 38% did not attend, but were unlikely to include many with further reactions. The question of natural history is important. Hill and colleagues quote data to show reactions became more severe in about 40% of patients, whereas this proportion was 1% in our series (of these only 0·18% or one per 567 had a severe reaction). Whether increased severity is a consequence of a larger dose of allergen (eating more nut) or a change in sensitivity is unknown, but the former factor is not taken into account in the work they cite. Whatever the reason, if nut avoidance is effective, this factor is less of an issue. Hill and colleagues’
THE LANCET • Vol 357 • April 7, 2001
concern about our selective provision of injectable epinephrine is not valid if a complete management strategy is used. Finally, Hill and colleagues criticise our use of inhaled epinephrine. We did not advocate this treatment for severe reactions, for which we used intramuscular epinephrine. We used inhaled epinephrine for its local effect on early mild laryngeal oedema (defined as a moderate or grade 4 reaction) and it was effective for 100% of treatments. Comments about absorption and blood concentrations of epinephrine after this route of administration are, therefore, irrelevant. Department of Allergy and Clinical Immunolgy, Clinic 2a, Box 40, Addenbrooke’s Hospital NHS Trust, Cambridge CB2 2QQ
primary endpoint of symptoms did not include reduced exercise tolerance (fatigue), which Hohnloser and colleagues note is associated with atrial fibrillation. Instead, this outcome was secondary, measured by exercise performance. Moreover, improvements in exercise performance in patients cardioverted to sinus rhythm were not reflected in the SF-36, a generic quality-of-life score. This assessment may not adequately reflect such differences between treatment groups. A key factor in restoring and sustaining sinus rhythm that is commonly overlooked is the speed at which treatment is started. We support opportunistic screening for atrial fibrillation in primary and secondary care by checking a patients’ pulse5 along with systems to enable fast referral and cardioversion if required.
1
*Roger A Harrison, Georgios Liratsopulos
*Pamela Ewan, Andrew Clark
2
Hill DJ, Heine RG, Hosking CS. Management of peanut and nut allergies. Lancet 2001; 357: 87–88. Ewan PW, Clark AT. Long-term prospective observational study of patients with peanut and nut allergy after participation in a management plan. Lancet 2001; 357: 111–15.
Directorate of Public Health, Wigan and Bolton Health Authority, Bryan House, Wigan WN1 1AH, UK (e-mail: [email protected]) 1
Atrial fibrillation control and cardioversion
2
Sir—Stefan Hohnloser and colleagues (Nov 25, p 1789)1 compared in an open study, rate control by diltiazem with cardioversion by amiodarone, with or without electrical cardioversion, for symptomatic persistent atrial fibrillation. Their main outcomes were symptom relief, exercise tolerance, and quality-of-life. They clearly state that this disorder does not necessarily have prognostic implications, and that treatment priority is to resolve symptoms. We suggest that many patients with persistent atrial fibrillation would prefer their five-fold risk of stroke, and increased risk of early mortality to be addressed before less severe symptoms.2 Epidemiological evidence strongly supports cardioversion for persistent atrial fibrillation.3 This practice should be continued until more mortality endpoints are reported. We are confused as to why patients restored to sinus rhythm remained on anticoagulation for the full study period, which raised their risk of bleeding, and might have masked potential improvements in quality of life.4 Anticoagulation is important for reducing embolic risk in atrial fibrillation only until patients have stable sinus rhythm. Finally, we are concerned that the
3
4
5
Hohnloser SH, Kuck K-H, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000; 356: 1789–94. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–52. Levy S, Breithardt G, Campbell RWF, et al. Atrial fibrillation: current knowledge and recommendations for management. Eur Heart J 1998; 19: 1294–320. Golzari H, Cebul RD, Bahler RC. Atrial fibrillation: restoration and maintenance of sinus rhythm and indicators for anticoagulation therapy. Ann Intern Med 1996; 125: 311–23. Baxter J, Crabtree L, Hildreth A, et al. Atrial fibrillation. Lancet 1998; 352: 1858.
Authors’ reply Sir—We agree with Roger Harrison and Georgios Liratsopulos that epidemiological data indicate prognostic implications associated with persistent or permanent atrial fibrillation, especially for thromboembolic complications. However, we know of no prospective trial supporting the notion that restoration and maintenance of sinus rhythm improves prognosis (ie, reduced mortality). Retrospective data show increased mortality in patients treated with antiarrhythmic drugs (particularly class I agents) compared with placebo.1 The advocation of restoration of sinus rhythm is not supported by scientific evidence. This dilemma prompted our study as well as the large atrial fibrillation follow-up investigation of rhythm management trial, which is powered to assess total mortality.2
1127
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
There are no data from prospective trials on when to stop anticoagulation after restoration of sinus rhythm. Some researchers recommend continuation of anticoagulation irrespective of the duration of sinus rhythm after cardioversion of atrial fibrillation.3 The rational for this approach is two-fold: first, the likelihood of recurrent atrial fibrillation is 50% or more within 3–6 months of successful cardioversion (even with preventive antiarrhythmic therapy), and, second, recurrences might be symptomless because of the rate-smoothing effects of other drugs. The risk of thromboembolism, is, of course, present; we used this rational to continue anticoagulation throughout our entire observation period. Exercise tolerance as an endpoint is discussed in our report. Rapid diagnosis is important, and we do not question this issue in our report. *Stefan H Hohnloser, Karl-Heinz Kuck J W Goethe-University, Department of Medicine and Department of Cardiology, 60590 Frankfurt, Germany (e-mail: [email protected]) 1
2
3
Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a metaanalysis of randomized controlled trials. Circulation 1990; 82: 1106. The Planning and Steering Committees of the AFFIRM Study for the NHLBI AFFIRM Investigators. Atrial fibrillation follow-up investigation of rhythm management: the AFFIRM study design. Am J Cardiol 1997; 79: 1198–202. Prystowski EN. Management of atrial fibrillation: therapeutic options and clinical decisions. Am J Cardiol 2000; 85: 3–11D.
Neonatal necropsy Sir—In your Jan 20 editorial1 you underscore the importance of necropsies and the need to educate the public. One feature of the debate about informed consent which has, however, been largely overlooked is the need to educate those who actually obtain consent. In 1988, a joint working party of representatives of relevant professional bodies stated that perinatal necropsy rates of lower than 75% were unacceptable, but in England, Wales, and Northern Ireland between 1993 and 1998, the necropsy rate for neonates declined from 47·6% to 41·2% (numbers are from the National Confidential Enquiry into Stillbirths and Deaths in Infancy). To maintain adequate rates of perinatal necropsy, systems to record numbers of deaths and necropsies, commitment on behalf of the clinical
1128
team, which implies a recognition of the potential benefits, and appropriate procedures to obtain consent are necessary. We attempted to obtain representative data relating to neonatal necropsy in 1997 and 1998 by a postal survey to the clinical directors of units that provide level III neonatal care. Of the 117 units identified in England, Scotland, and Wales we received replies from 110 units. Only 11% had no access to a pathologist with an interest in perinatal pathology. Units were asked what they considered an acceptable neonatal necropsy rate; answers ranged from 25% to 100%, with a third of units suggesting at least 75%. Just fewer than a quarter of units were unable to provide the actual number of neonatal deaths, and 26% could provide no data on the number of necropsies done. Only 56% of responders could say how many parents had been approached and either consented or refused the request. We asked for comments about necropsy. These included statements that necropsy should be undertaken only if it benefited the family or if the cause of death was uncertain, and that it was inappropriate for babies who were extremely premature or who had known congenital malformations. One unit commented that consent was requested depending on the certainty of the diagnosis. These statements ignore the frequency with which neonatal necropsy provides additional unexpected diagnostic and audit information,2 and the fact that some families value necropsy for grieving and assuaging feelings of guilt.3 Requests for necropsies of neonates were made by consultants in only 16% of units. Sensitive approach by a professional who is aware of practical features and benefits to families and carers can increase necropsy rates.4 A failure to address these misperceptions and the declining trend in necropsy rates will in the long-term adversely affect clinical care. Ultimately, as Doyle2 suggests, the perinatal necropsy could become a lost skill. *Christopher Wright, Alan Fenton, Nicholas Embleton *Department of Pathology and Neonatal Unit, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK 1 2 3
4
Editorial. Retention of organs after necropsy. Lancet 2001; 357: 157. Doyle LW. Effects of perinatal autopsy on counselling. Lancet 2000; 355: 2093. Beckwith JB. The value of the paediatric postmortem examination. Pediatr Clin North Am 1989; 36: 2–36. Lugli A, Anabitarte M, Beer JH. Effect of simple interventions on necropsy rate when active informed consent is required. Lancet 1999; 354: 1391.
High-dose cyclophosphamide in aplastic anaemia Sir—John Tisdale and colleagues (Nov 4, p 1554)1 report that high-dose cyclophosphamide is a dangerous choice for treating aplastic anaemia. They randomly assigned 31 patients cyclophosphamide plus ciclosporin or antithymocite immunoglobulin plus ciclosporin and stopped the study early because of increased toxic effects in the cyclophosphamide group. The management of aplastic anaemia must take into account early and late morbidity and mortality from incomplete treatment of the disease. Clearly, allogeneic bone-marrow transplant for many diseases (eg, chronic myelogenous leukaemia) has higher early morbidity than nontransplant therapy. Moreover, the survival advantage for the procedure is frequently not apparent for several years. Most aplastic anaemia patients treated with antithymocyte globulin plus ciclosporin will develop late complications such as relapse, dependence on immunosuppressive therapy, or late clonal disease.2,3 Consequently, the survival advantage of bone-marrow transplant over immunosuppressive therapy does not become apparent in aplastic anaemia for 2–4 years.4 Similar to allogeneic bone-marrow transplant, a major advantage of high-dose cyclophosphamide over antithymocyte immunoglobulin plus ciclosporin is the potential to produce long-term treatment-free remissions, as we showed in seven of ten patients.5 We have since treated many additional severe aplastic anaemia patients (median age 47, 50% with very severe disease) with cyclophosphamide alone as primary therapy. Most patients’ blood counts have normalised and treatment has been stopped. Fewer than 10% of the patients have developed fungal infections, and only 15% have died. We know of no relapses, clonal disorders, or need for additional therapy to maintain the response. Response to cyclophosphamide is gradual; the time to response (transfusion independence) can be 6 months to 1 year, and to complete response (normalisation of blood counts) can be 2–3 years. The patients in our original study have a median follow-up of 14 years and, therefore, are cured. Tisdale and colleagues stopped their study early, despite reaching no primary or secondary endpoint.
THE LANCET • Vol 357 • April 7, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
2
3
4
Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask. JAMA 2000; 284: 2352–60. Rusterholtz T, Kempf J, Berton C, et al. Noninvasive pressure support ventilation (NIPSV) with face mask in patients with acute pulmonary edema (ACPE). Intensive Care Med 1999; 25: 21–28. Carbone G, Di Battista N, Nava S, Noninvasive bilevel ventilation vs conventional therapy in the treatment of acute cardiogenic pulmonary oedema: a randomised study. Eur Respir J 2000; 16: A3815.
Management of peanut and nut allergy Sir—David Hill and colleagues in their Jan 13 Commentary1 feel it premature to adopt our management plan for nut allergy,2 but they have missed the point. The evidence they quote from other studies: that, in patients with peanut and nut allergy, further reactions occur in 50–58% and that mild-index reactions are followed by severe reactions in 38–44%, surely underline the effectiveness of our treatment plan. In our study, only 15% of patients had further reactions, most of which were mild. This finding suggests that the avoidance arm of our protocol was effective. Hill and colleagues focus on drug treatment of reactions only, whereas we advocate an overall strategy including prevention of further reactions. Hill and colleagues are concerned that the outcome may have been favourably affected by resolution of the allergy (a factor we discussed) or incorrect diagnosis, but these factors would also apply to the other series. They wonder whether our results were influenced by the 154 patients not followed up: 62% had not reached their first follow-up appointment so no data had been obtained; 38% did not attend, but were unlikely to include many with further reactions. The question of natural history is important. Hill and colleagues quote data to show reactions became more severe in about 40% of patients, whereas this proportion was 1% in our series (of these only 0·18% or one per 567 had a severe reaction). Whether increased severity is a consequence of a larger dose of allergen (eating more nut) or a change in sensitivity is unknown, but the former factor is not taken into account in the work they cite. Whatever the reason, if nut avoidance is effective, this factor is less of an issue. Hill and colleagues’
THE LANCET • Vol 357 • April 7, 2001
concern about our selective provision of injectable epinephrine is not valid if a complete management strategy is used. Finally, Hill and colleagues criticise our use of inhaled epinephrine. We did not advocate this treatment for severe reactions, for which we used intramuscular epinephrine. We used inhaled epinephrine for its local effect on early mild laryngeal oedema (defined as a moderate or grade 4 reaction) and it was effective for 100% of treatments. Comments about absorption and blood concentrations of epinephrine after this route of administration are, therefore, irrelevant. Department of Allergy and Clinical Immunolgy, Clinic 2a, Box 40, Addenbrooke’s Hospital NHS Trust, Cambridge CB2 2QQ
primary endpoint of symptoms did not include reduced exercise tolerance (fatigue), which Hohnloser and colleagues note is associated with atrial fibrillation. Instead, this outcome was secondary, measured by exercise performance. Moreover, improvements in exercise performance in patients cardioverted to sinus rhythm were not reflected in the SF-36, a generic quality-of-life score. This assessment may not adequately reflect such differences between treatment groups. A key factor in restoring and sustaining sinus rhythm that is commonly overlooked is the speed at which treatment is started. We support opportunistic screening for atrial fibrillation in primary and secondary care by checking a patients’ pulse5 along with systems to enable fast referral and cardioversion if required.
1
*Roger A Harrison, Georgios Liratsopulos
*Pamela Ewan, Andrew Clark
2
Hill DJ, Heine RG, Hosking CS. Management of peanut and nut allergies. Lancet 2001; 357: 87–88. Ewan PW, Clark AT. Long-term prospective observational study of patients with peanut and nut allergy after participation in a management plan. Lancet 2001; 357: 111–15.
Directorate of Public Health, Wigan and Bolton Health Authority, Bryan House, Wigan WN1 1AH, UK (e-mail: [email protected]) 1
Atrial fibrillation control and cardioversion
2
Sir—Stefan Hohnloser and colleagues (Nov 25, p 1789)1 compared in an open study, rate control by diltiazem with cardioversion by amiodarone, with or without electrical cardioversion, for symptomatic persistent atrial fibrillation. Their main outcomes were symptom relief, exercise tolerance, and quality-of-life. They clearly state that this disorder does not necessarily have prognostic implications, and that treatment priority is to resolve symptoms. We suggest that many patients with persistent atrial fibrillation would prefer their five-fold risk of stroke, and increased risk of early mortality to be addressed before less severe symptoms.2 Epidemiological evidence strongly supports cardioversion for persistent atrial fibrillation.3 This practice should be continued until more mortality endpoints are reported. We are confused as to why patients restored to sinus rhythm remained on anticoagulation for the full study period, which raised their risk of bleeding, and might have masked potential improvements in quality of life.4 Anticoagulation is important for reducing embolic risk in atrial fibrillation only until patients have stable sinus rhythm. Finally, we are concerned that the
3
4
5
Hohnloser SH, Kuck K-H, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000; 356: 1789–94. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–52. Levy S, Breithardt G, Campbell RWF, et al. Atrial fibrillation: current knowledge and recommendations for management. Eur Heart J 1998; 19: 1294–320. Golzari H, Cebul RD, Bahler RC. Atrial fibrillation: restoration and maintenance of sinus rhythm and indicators for anticoagulation therapy. Ann Intern Med 1996; 125: 311–23. Baxter J, Crabtree L, Hildreth A, et al. Atrial fibrillation. Lancet 1998; 352: 1858.
Authors’ reply Sir—We agree with Roger Harrison and Georgios Liratsopulos that epidemiological data indicate prognostic implications associated with persistent or permanent atrial fibrillation, especially for thromboembolic complications. However, we know of no prospective trial supporting the notion that restoration and maintenance of sinus rhythm improves prognosis (ie, reduced mortality). Retrospective data show increased mortality in patients treated with antiarrhythmic drugs (particularly class I agents) compared with placebo.1 The advocation of restoration of sinus rhythm is not supported by scientific evidence. This dilemma prompted our study as well as the large atrial fibrillation follow-up investigation of rhythm management trial, which is powered to assess total mortality.2
1127
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
There are no data from prospective trials on when to stop anticoagulation after restoration of sinus rhythm. Some researchers recommend continuation of anticoagulation irrespective of the duration of sinus rhythm after cardioversion of atrial fibrillation.3 The rational for this approach is two-fold: first, the likelihood of recurrent atrial fibrillation is 50% or more within 3–6 months of successful cardioversion (even with preventive antiarrhythmic therapy), and, second, recurrences might be symptomless because of the rate-smoothing effects of other drugs. The risk of thromboembolism, is, of course, present; we used this rational to continue anticoagulation throughout our entire observation period. Exercise tolerance as an endpoint is discussed in our report. Rapid diagnosis is important, and we do not question this issue in our report. *Stefan H Hohnloser, Karl-Heinz Kuck J W Goethe-University, Department of Medicine and Department of Cardiology, 60590 Frankfurt, Germany (e-mail: [email protected]) 1
2
3
Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a metaanalysis of randomized controlled trials. Circulation 1990; 82: 1106. The Planning and Steering Committees of the AFFIRM Study for the NHLBI AFFIRM Investigators. Atrial fibrillation follow-up investigation of rhythm management: the AFFIRM study design. Am J Cardiol 1997; 79: 1198–202. Prystowski EN. Management of atrial fibrillation: therapeutic options and clinical decisions. Am J Cardiol 2000; 85: 3–11D.
Neonatal necropsy Sir—In your Jan 20 editorial1 you underscore the importance of necropsies and the need to educate the public. One feature of the debate about informed consent which has, however, been largely overlooked is the need to educate those who actually obtain consent. In 1988, a joint working party of representatives of relevant professional bodies stated that perinatal necropsy rates of lower than 75% were unacceptable, but in England, Wales, and Northern Ireland between 1993 and 1998, the necropsy rate for neonates declined from 47·6% to 41·2% (numbers are from the National Confidential Enquiry into Stillbirths and Deaths in Infancy). To maintain adequate rates of perinatal necropsy, systems to record numbers of deaths and necropsies, commitment on behalf of the clinical
1128
team, which implies a recognition of the potential benefits, and appropriate procedures to obtain consent are necessary. We attempted to obtain representative data relating to neonatal necropsy in 1997 and 1998 by a postal survey to the clinical directors of units that provide level III neonatal care. Of the 117 units identified in England, Scotland, and Wales we received replies from 110 units. Only 11% had no access to a pathologist with an interest in perinatal pathology. Units were asked what they considered an acceptable neonatal necropsy rate; answers ranged from 25% to 100%, with a third of units suggesting at least 75%. Just fewer than a quarter of units were unable to provide the actual number of neonatal deaths, and 26% could provide no data on the number of necropsies done. Only 56% of responders could say how many parents had been approached and either consented or refused the request. We asked for comments about necropsy. These included statements that necropsy should be undertaken only if it benefited the family or if the cause of death was uncertain, and that it was inappropriate for babies who were extremely premature or who had known congenital malformations. One unit commented that consent was requested depending on the certainty of the diagnosis. These statements ignore the frequency with which neonatal necropsy provides additional unexpected diagnostic and audit information,2 and the fact that some families value necropsy for grieving and assuaging feelings of guilt.3 Requests for necropsies of neonates were made by consultants in only 16% of units. Sensitive approach by a professional who is aware of practical features and benefits to families and carers can increase necropsy rates.4 A failure to address these misperceptions and the declining trend in necropsy rates will in the long-term adversely affect clinical care. Ultimately, as Doyle2 suggests, the perinatal necropsy could become a lost skill. *Christopher Wright, Alan Fenton, Nicholas Embleton *Department of Pathology and Neonatal Unit, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK 1 2 3
4
Editorial. Retention of organs after necropsy. Lancet 2001; 357: 157. Doyle LW. Effects of perinatal autopsy on counselling. Lancet 2000; 355: 2093. Beckwith JB. The value of the paediatric postmortem examination. Pediatr Clin North Am 1989; 36: 2–36. Lugli A, Anabitarte M, Beer JH. Effect of simple interventions on necropsy rate when active informed consent is required. Lancet 1999; 354: 1391.
High-dose cyclophosphamide in aplastic anaemia Sir—John Tisdale and colleagues (Nov 4, p 1554)1 report that high-dose cyclophosphamide is a dangerous choice for treating aplastic anaemia. They randomly assigned 31 patients cyclophosphamide plus ciclosporin or antithymocite immunoglobulin plus ciclosporin and stopped the study early because of increased toxic effects in the cyclophosphamide group. The management of aplastic anaemia must take into account early and late morbidity and mortality from incomplete treatment of the disease. Clearly, allogeneic bone-marrow transplant for many diseases (eg, chronic myelogenous leukaemia) has higher early morbidity than nontransplant therapy. Moreover, the survival advantage for the procedure is frequently not apparent for several years. Most aplastic anaemia patients treated with antithymocyte globulin plus ciclosporin will develop late complications such as relapse, dependence on immunosuppressive therapy, or late clonal disease.2,3 Consequently, the survival advantage of bone-marrow transplant over immunosuppressive therapy does not become apparent in aplastic anaemia for 2–4 years.4 Similar to allogeneic bone-marrow transplant, a major advantage of high-dose cyclophosphamide over antithymocyte immunoglobulin plus ciclosporin is the potential to produce long-term treatment-free remissions, as we showed in seven of ten patients.5 We have since treated many additional severe aplastic anaemia patients (median age 47, 50% with very severe disease) with cyclophosphamide alone as primary therapy. Most patients’ blood counts have normalised and treatment has been stopped. Fewer than 10% of the patients have developed fungal infections, and only 15% have died. We know of no relapses, clonal disorders, or need for additional therapy to maintain the response. Response to cyclophosphamide is gradual; the time to response (transfusion independence) can be 6 months to 1 year, and to complete response (normalisation of blood counts) can be 2–3 years. The patients in our original study have a median follow-up of 14 years and, therefore, are cured. Tisdale and colleagues stopped their study early, despite reaching no primary or secondary endpoint.
THE LANCET • Vol 357 • April 7, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.