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Is it refractory idiopathic thrombocytopenic purpura?
THE LANCET
cardiac (non-arrhythmic) death, since the monitor shows a picture compatible with electromechanical dissociation. If no monitor strip had been available, the definition would have been arrhythmic death, diluting the power of the study to assess the effect of amiodarone on arrhythmic death, but not subject to bias with the rigorous procedures that were in place. In any case, the emphasis on a single patient anecdote by contrast with randomised controlled data on 1202 patients in CAMIAT and 1486 patients in EMIAT is surprising to say the least. *John A Cairns, Stuar t J Connolly, Robin Rober ts, Michael Gent, on behalf of the CAMIAT Investigators Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z 3
1
2
3
Hinkle LE Jr, Thaler HT. Clinical classification of cardiac deaths. Circulation 1982; 65: 457–64. Gottlieb SS. Dead is dead: artificial definitions are no substitute. Lancet 1997; 349: 662–63. Cairns JA, Connolly SJ, Roberts RS, Gent M. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT): rationale and protocol. Am J Cardiol 1993; 72: 87F–94F.
Commentator’s reply SIR—Despite the justifications and explanations of some of your correspondents, we should remember that CAMIAT1 and EMIAT2 were negative studies with respect to total mortality and that the isolated endpoint of sudden death is not clinically relevant. The findings do not exclude the importance of arrhythmias as a cause of morality, and I agree with Malik and Camm that it is appropriate to address the problem of arrhythmic death by selecting high-risk patients and evaluating the effects of an intervention. Perhaps they are even correct in assuming that patients with a high risk of arrhythmic (rather than general) mortality need to be studied (if such a group can be defined). However, until and unless total mortality is decreased in a defined population, a conclusion that the clinician should be “encouraged to consider amiodarone” does not seem warranted. Many of your correspondents continue to disregard the fact that sudden death is not equivalent to arrhythmic death, even if obvious cases of ischaemia or progressive heart failure are excluded. Deaths from myocardial infarctions, pulmonary emboli, and a host of other causes will be sudden, and may be a large proportion of these deaths. Conversely, a patient with ischaemia or heart failure could have a preventable arrhythmic death despite having other cardiac symptoms. Norris’ use of a study in which death was
1770
arbitrarily classified to prove that arbitrary classifications are beneficial is tautologous and not proof of this point, Although the proportion of arrhythmic deaths may be different in patients with heart failure than in those post myocardial infarction, the interaction between these two diseases is considerable. Indeed, Norris clearly realises the close connection between these diseases by proposing studies in patients with poor left ventricular function. I agree that the positive interaction of amiodarone and blockade is intriguing and deserves further investigation, especially in patients with heart failure. Of course, these studies must be powered to detect an improvement in total mortality. We should appreciate Cleland and Erhardt’s attempts at making sense of classification of death. The use of classification to try to understand physiology and the reasons behind an effect and to generate hypotheses may well be useful. As I am sure these workers would agree, however, the use of classification of sudden death as a justification for the use of a drug which does not affect mortality, is quite another matter. Julian and colleagues attempt to justify their study design by analogy to early studies of aspirin and lipidlowering agents which used causespecific benefits to lead to the larger more conclusive studies. However, the notion of amiodarone use post myocardial infarction is well past the early stage of investigation, with a metaanalysis (cited in the CAMIAT article) already suggesting mortality benefit.3 At this stage, large expensive studies should not be underpowered and designed to look at clinically unimportant and potentially misleading endpoints. Cairns and colleagues are correct in saying that “the most definitive evidence of overall drug benefit is provided by a statistically significant reduction of all-cause mortality”. We did not need another small study to be part of a metaanalysis. Stephen S Gottlieb Depar tment of Medicine, University of Mar yland School of Medicine, Baltimore, MD 21201, USA
1
2
3
Cairns JA, Connolly SJ, Roberts R, Gent M. Randomized trial of outcomes after myocardial infarction in patients with frequent to repetitive ventricular premature depolarizations. CAMIAT. Lancet 1997; 349: 675–82. Julian DG, Camm AJ, Frangin G, et al. Randomized trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349: 667–74. Teo KK,Yusaf S, Furbrug CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomised controlled clinical trials. JAMA 1993; 270: 1589–95
Is it refractory idiopathic thrombocytopenic purpura? SIR—Cahill and Newland (April 12, p 1066)1 diagnose Epstein’s syndrome, but without reporting the electronmicroscopic finding of the kidney biopsy sample, the family history, and genetic study of their patient. As they mention, crescentic glomerulonephritis is not a feature of Alport or Epstein’s syndrome. The main finding in these syndromes is the electronmicroscopic finding of kidney biopsy sample showing variable thickening-thinning, lamellation, and basket-weaving of the glomerular basement membrane.2 In addition, the deafness in Alport and Epstein’s syndrome is characterised by progressive loss of sensorineural hearing3 and not by recurrent otitis media, as seems to be the case from this report. Alport syndrome is transmitted in X-linked dominant or autosomal recessive pattern with the defects in the gene COL4A5 in the long arm of the X chromosome or COL4A3 or COL4A4 on chromosome 2.2 Therefore, the family history is of crucial importance. Has a genetic investigation been conducted in the patient’s family? Ocular changes, icthyosis, atopic dermatitis, and leiomyomatosis can also occur in Alport and Epstein’s syndromes;3 does the patient have any of these features? Pairach Pintavorn Southern Jersey Medical Center Inc, Pleasantville, NJ 08201, USA
1
2
3
Cahill MR, Newland AC. Is it refractory idiopathic thrombocytopenic purpura? Lancet 1997; 349: 1066. Churg J, Bernstein J, Glassock RJ. Alport syndrome. In: Churg J, Bernstein J, Glassock RJ, eds. Renal disease: classification and atlas of glomerular disease. Igaku-Shoin Medical Publishers, 1995: 409–11. Kashtan CE. Alport syndrome. In: Massry SG, Glassock RJ, eds. Textbook of nephrology. Baltimore: Williams and Wilkins, 1995: 869–72.
Authors’ reply SIR—In our patient with a macrothrombocytopathy, deafness, and glomerulonephritis, Epstein’s syndrome is the most likely diagnosis. There was no family history, and full blood counts on the parents, sibling, and other close relatives were normal. However, both an autosomal recessive condition and a new mutation are consistent with this information, and although genetic studies might be persuasive, working clinical diagnoses without genetic confirmation are commonly relied on to guide treatment. The patient has severe progressive sensorineural deafness and is dependent on the use of a combination of bilateral hearing aids and lip reading.
Vol 349 • June 14, 1997
cardiac (non-arrhythmic) death, since the monitor shows a picture compatible with electromechanical dissociation. If no monitor strip had been available, the definition would have been arrhythmic death, diluting the power of the study to assess the effect of amiodarone on arrhythmic death, but not subject to bias with the rigorous procedures that were in place. In any case, the emphasis on a single patient anecdote by contrast with randomised controlled data on 1202 patients in CAMIAT and 1486 patients in EMIAT is surprising to say the least. *John A Cairns, Stuar t J Connolly, Robin Rober ts, Michael Gent, on behalf of the CAMIAT Investigators Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z 3
1
2
3
Hinkle LE Jr, Thaler HT. Clinical classification of cardiac deaths. Circulation 1982; 65: 457–64. Gottlieb SS. Dead is dead: artificial definitions are no substitute. Lancet 1997; 349: 662–63. Cairns JA, Connolly SJ, Roberts RS, Gent M. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT): rationale and protocol. Am J Cardiol 1993; 72: 87F–94F.
Commentator’s reply SIR—Despite the justifications and explanations of some of your correspondents, we should remember that CAMIAT1 and EMIAT2 were negative studies with respect to total mortality and that the isolated endpoint of sudden death is not clinically relevant. The findings do not exclude the importance of arrhythmias as a cause of morality, and I agree with Malik and Camm that it is appropriate to address the problem of arrhythmic death by selecting high-risk patients and evaluating the effects of an intervention. Perhaps they are even correct in assuming that patients with a high risk of arrhythmic (rather than general) mortality need to be studied (if such a group can be defined). However, until and unless total mortality is decreased in a defined population, a conclusion that the clinician should be “encouraged to consider amiodarone” does not seem warranted. Many of your correspondents continue to disregard the fact that sudden death is not equivalent to arrhythmic death, even if obvious cases of ischaemia or progressive heart failure are excluded. Deaths from myocardial infarctions, pulmonary emboli, and a host of other causes will be sudden, and may be a large proportion of these deaths. Conversely, a patient with ischaemia or heart failure could have a preventable arrhythmic death despite having other cardiac symptoms. Norris’ use of a study in which death was
1770
arbitrarily classified to prove that arbitrary classifications are beneficial is tautologous and not proof of this point, Although the proportion of arrhythmic deaths may be different in patients with heart failure than in those post myocardial infarction, the interaction between these two diseases is considerable. Indeed, Norris clearly realises the close connection between these diseases by proposing studies in patients with poor left ventricular function. I agree that the positive interaction of amiodarone and blockade is intriguing and deserves further investigation, especially in patients with heart failure. Of course, these studies must be powered to detect an improvement in total mortality. We should appreciate Cleland and Erhardt’s attempts at making sense of classification of death. The use of classification to try to understand physiology and the reasons behind an effect and to generate hypotheses may well be useful. As I am sure these workers would agree, however, the use of classification of sudden death as a justification for the use of a drug which does not affect mortality, is quite another matter. Julian and colleagues attempt to justify their study design by analogy to early studies of aspirin and lipidlowering agents which used causespecific benefits to lead to the larger more conclusive studies. However, the notion of amiodarone use post myocardial infarction is well past the early stage of investigation, with a metaanalysis (cited in the CAMIAT article) already suggesting mortality benefit.3 At this stage, large expensive studies should not be underpowered and designed to look at clinically unimportant and potentially misleading endpoints. Cairns and colleagues are correct in saying that “the most definitive evidence of overall drug benefit is provided by a statistically significant reduction of all-cause mortality”. We did not need another small study to be part of a metaanalysis. Stephen S Gottlieb Depar tment of Medicine, University of Mar yland School of Medicine, Baltimore, MD 21201, USA
1
2
3
Cairns JA, Connolly SJ, Roberts R, Gent M. Randomized trial of outcomes after myocardial infarction in patients with frequent to repetitive ventricular premature depolarizations. CAMIAT. Lancet 1997; 349: 675–82. Julian DG, Camm AJ, Frangin G, et al. Randomized trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349: 667–74. Teo KK,Yusaf S, Furbrug CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomised controlled clinical trials. JAMA 1993; 270: 1589–95
Is it refractory idiopathic thrombocytopenic purpura? SIR—Cahill and Newland (April 12, p 1066)1 diagnose Epstein’s syndrome, but without reporting the electronmicroscopic finding of the kidney biopsy sample, the family history, and genetic study of their patient. As they mention, crescentic glomerulonephritis is not a feature of Alport or Epstein’s syndrome. The main finding in these syndromes is the electronmicroscopic finding of kidney biopsy sample showing variable thickening-thinning, lamellation, and basket-weaving of the glomerular basement membrane.2 In addition, the deafness in Alport and Epstein’s syndrome is characterised by progressive loss of sensorineural hearing3 and not by recurrent otitis media, as seems to be the case from this report. Alport syndrome is transmitted in X-linked dominant or autosomal recessive pattern with the defects in the gene COL4A5 in the long arm of the X chromosome or COL4A3 or COL4A4 on chromosome 2.2 Therefore, the family history is of crucial importance. Has a genetic investigation been conducted in the patient’s family? Ocular changes, icthyosis, atopic dermatitis, and leiomyomatosis can also occur in Alport and Epstein’s syndromes;3 does the patient have any of these features? Pairach Pintavorn Southern Jersey Medical Center Inc, Pleasantville, NJ 08201, USA
1
2
3
Cahill MR, Newland AC. Is it refractory idiopathic thrombocytopenic purpura? Lancet 1997; 349: 1066. Churg J, Bernstein J, Glassock RJ. Alport syndrome. In: Churg J, Bernstein J, Glassock RJ, eds. Renal disease: classification and atlas of glomerular disease. Igaku-Shoin Medical Publishers, 1995: 409–11. Kashtan CE. Alport syndrome. In: Massry SG, Glassock RJ, eds. Textbook of nephrology. Baltimore: Williams and Wilkins, 1995: 869–72.
Authors’ reply SIR—In our patient with a macrothrombocytopathy, deafness, and glomerulonephritis, Epstein’s syndrome is the most likely diagnosis. There was no family history, and full blood counts on the parents, sibling, and other close relatives were normal. However, both an autosomal recessive condition and a new mutation are consistent with this information, and although genetic studies might be persuasive, working clinical diagnoses without genetic confirmation are commonly relied on to guide treatment. The patient has severe progressive sensorineural deafness and is dependent on the use of a combination of bilateral hearing aids and lip reading.
Vol 349 • June 14, 1997