- Email: [email protected]
Sickle-cell disease and the patient
Correspondence
Science Photo Library
Authors’ reply
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
382
We agree with Peter Bogaty and James Brophy with respect to the usefulness of thienopyridines in acute coronary syndromes without STelevation. However, our conservative patients did not receive these drugs, since there is as yet neither evidence nor recommendation for their use in the setting of ST-elevated acute myocardial infarction (STEMI) treated without angioplasty.1 Their arguments about predischarge revascularisation constitute a clear sophism, which tendentiously ignores the well-proven import of early mechanical repair of the infarctrelated artery.2 Similarly, the example of prophylactic appendectomy is as rhetorical as it is wrong. One could stretch Bogaty and Brophy’s example to the absurd extent that randomised trials to compare primary angioplasty and thrombolysis2 should consider primary angioplasty an adverse event. Nonetheless, we maintain that we have not compared specific treatments but rather two different strategies for patients with heart attack (the equivalent to diagnosed acute appendicitis, in Bogaty and Brophy’s example). With this point in mind, early anatomy-based revascularisation constituted the essence of the invasive strategy, whereas predischarge ischaemia-driven revascularisation was seen as an inseparable part of the so-called ischaemia-guided conservative strategy. Both approaches had to be completed in every patient before their effect in preventing further events could be compared, and we established discharge as the moment from which the components of the primary endpoint had to be counted. Therefore, we analysed predischarge ischaemiadriven revascularisation in the conservative group as a secondary endpoint, but did not consider it as part of the primary endpoint. No patient in the invasive-treatment group needed planned ischaemiadriven revascularisation before dis-
charge. By contrast, 21 patients in the conservative-treatment group underwent predischarge planned revascularisation due to stressinduced ischaemia (8% vs 0%, p0·001). Most importantly, conservative patients had more in-hospital unplanned revascularisations induced by spontaneous ischaemia (12% vs 2%, relative risk 0·20, 95% CI 0·09–0·48, p0·001). Therefore, if we had included in the primary endpoint ischaemia-driven revascularisations done before discharge, the incidence of the primary endpoint at 1 year would have been 9% in the invasive group and 41% in the conservative group (relative risk 0·15, 0·08–0·24, p0·001), representing a risk reduction of 85% in favour of the interventional group, which is clearly higher than we observed with our design. The early post-thrombolysis interventional approach safely allows risk stratification, shortens hospital stay, and seems to improve outcome. Consequently, to think that this strategy might be preferable to a conservative one is reasonable. Furthermore, this approach reduces early recurrence of spontaneous ischaemic events. This beneficial effect on such an ominous complication coincides with the meta-analysis by Gibson3 on the outcome of 20 101 patients with thrombolysed STEMI, the results of which show that early post-thrombolysis reinfarction is associated with increased mortality up to 2 years and that early routine intervention reduces both risk of early reinfarction and 2-year mortality. Finally, the GRACIA strategy can be safely applied in hospitals without a cath-lab in coordination with tertiary centres. Thus, the approach might represent an acceptable alternative for the still high proportion of patients with STEMI for whom the gold standard of care (primary angioplasty) is not available for logistical reasons.4 This scenario makes sense even from a public-payer perspective.
We declare that we have no conflict of interest.
*Francisco Fernández-Avilés, Pedro L Sánchez, on behalf of the GRACIA Group [email protected] Insitituto de Ciencias del Corazón (ICICOR), University Hospital, School of Medicine, Valladolid, Spain 1
2
3
4
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary. Circulation 2004; 110: 588–636. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13–20. Gibson CM, Karha J, Murphy SA, et al. Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis In Myocardial Infarction Trials. J Am Coll Cardiol 2003; 42: 7–16. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin: the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23: 1190–201.
Sickle-cell disease and the patient Marie Stuart and Ronald Nagel’s Seminar (Oct 9, p 1343)1 and Michaela Buckner’s Personal Account (p 1361)2 highlight the differences between sickle-cell disease and the patient. Michaela need not worry about the disease being “a systemic disorder of monumental complexity”,1 because the patient is far from complex. Three of my siblings had sickle-cell disease (chwechweechwe),3 which can be traced back in my family to 1670 (family tree available at http://www. sicklecell.md/images/generation.jpg). Stuart and Nagel missed something out of their Seminar, which Michaela emphasises—circumstances. “The dreaded malaria” and “wearing [. . . ] traditional African clothes in December in the UK”2 that Michaela describes are known causes of sicklecell crises.3–5 A child I treated who was homozygous for the disease had a www.thelancet.com Vol 365 January 29, 2005
Correspondence
www.thelancet.com Vol 365 January 29, 2005
Work on transgenic mice might answer some of the questions about sickle-cell disease, but will probably never be able to explain why one of my patients went into severe crisis on hearing that his mother had died.3 I declare that I have no conflict of interest.
Felix I D Konotey-Ahulu [email protected] Department of Tropical Medicine, Cromwell Hospital, London SW5 0TU, UK 1 2
3
4
5
Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004; 364: 1343–60. Buckner M. Sickle-cell disease: from Sierra Leone to southeast London. Lancet 2004; 364: 1361. Konotey-Ahulu FID. The sickle cell disease patient: natural history from a clinicoepidemiological study of the first 1550 patients of Korle Bu Hospital Sickle Cell Clinic. Watford: Tetteh-A’Domeno, 1996. Konotey-Ahulu FID. The sickle cell diseases: clinical manifestations including the “Sickle Crisis”. Arch Intern Med 1974; 133: 611–19. Konotey-Ahulu FID. Effect of environment on sickle cell disease in West Africa: epidemiologic and clinical considerations. In: Abramson H, Bertles JF, Wethers DL, eds. Sickle cell disease, diagnosis, management, education, and research. St Louis: The C V Mosby Company, 1973: 20–38.
within the eligible cohort seems to be about 15% lower in the intervention areas (2972/14 8881000=199·7) than in control areas (3303/14 047 1000=235·1). Such a difference in fertility might also imply differences in birth interval, either related to preexisting differences between the intervention and control areas or to the intervention itself, by enhancing demand or improving existing family planning services. The 2001 DHS for Nepal noted that 60% of birth intervals were less than 3 years, and 23% were less than 2 years.3 Although contraceptive prevalence was 39% nationally in 2001, unmet need for family planning was still 16% for limiting births and 11% for spacing. Although birth spacing cannot account for the large difference in neonatal mortality seen in the Manandhar study, it could have contributed substantially. In any case, to be credible, studies on the effect of child survival interventions should take the important effect of birth interval into account. I declare that I have no conflict of interest.
Birth spacing and neonatal mortality Manandhar and colleagues’ article (Sept 11, p 970)1 on the effect of women’s groups in Nepal represents progress in the challenge to reduce neonatal mortality in the developing world. Surprisingly, however, birth spacing is not addressed. Birth spacing is increasingly recognised as a major determinant of various infant health indicators, including neonatal mortality. Analysis of Demographic and Health Surveys (DHS) from around the developing world, controlling for various potential confounders, indicates neonatal mortality is reduced by roughly 40% for preceding birth intervals of 3 years or more, compared with intervals of less than 2 years.2 Manandhar and colleagues’ data suggest important fertility differences between their intervention and control areas. Notably, the general fertility rate
James D Shelton [email protected] Bureau for Global Health, Agency for International Development, Washington, DC 2523, USA 1
2
3
Manandhar DS, Osrin D, Shrestha BP, et al. Effect of a participatory intervention with women’s groups on birth outcomes in Nepal: cluster-randomised controlled trial. Lancet 2004; 364: 970–79. Setty-Venugopal V, Upadhyay UD. Birth spacing: three to five saves lives. Baltimore: Johns Hopkins University, Population Information Program, 2002. Ministry of Health, Nepal, New Era, and ORC Macro. Nepal demographic and health survey 2001. Kathmandu: Calverton, 2002.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Authors’ reply James Shelton raises three important points about short birth intervals and neonatal mortality in developing countries. First, he points out the increased neonatal mortality associated with short birth intervals. In the Makwanpur trial the neonatal mortality rate was 42 per 1000 (43/1030 livebirths; 95% CI 29–54) in mothers 383
Panos Pictures
stroke because his grandmother took him out without an overcoat; his identical twin, who stayed at home, was not saved by cation homoeostasis1 or variations in vascular cell adhesion molecule-1 (VCAM-1) bonding to the endothelium via 41. My ancestors3 knew the difference between “gbagblaa” (SS-phenotype) and “pi-gbagblaa”, SC-phenotype,4 and made sure that survival was optimised through the rigourous observation of specific circumstances .3–5 One in 16 women with an increased rate of urinary tract infections in pregnancy and one in four men, is homozygous and hemizygous, respectively, for glucouse 6-phosphate dehydrogenase (G6PD) deficiency,3–5 jeopardising antimicrobial therapy.5 If Michaela Buckner is homozygous for G6PD deficiency, then both her children will be hemizygous; if heterozygous, the son with the more severe disease could well be the one carrying her G6PD-deficient gene.5 By keeping a detailed diary, she should soon find what tips them into crisis. She should try to meet patients with sickle-cell disease who manage without hydroxyurea and diamorphine or morphine for crisis pain and ask them how. Clinicians should assess new presenting symptoms, such as gnathopathy,3–5 the numb lower lip,3,4 and accelerated finger clubbing,3 and seek information about how patients are treating themselves. When a patient who is able to manage their disease without drugs claims that a nutrient like aerobic oxygen has kept them symptom-free for decades, doctors should pay attention. Antibiotics, folic acid, pneumovaccine, plenty of water, a good community nurse, family doctors that listen, together with strict attention to circumstances, will help keep Michaela’s boys out of hospital. She should teach them that half their children will have sickle-cell disease if they marry someone with the trait, which one in three west Africans carries.3–5
Science Photo Library
Authors’ reply
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
382
We agree with Peter Bogaty and James Brophy with respect to the usefulness of thienopyridines in acute coronary syndromes without STelevation. However, our conservative patients did not receive these drugs, since there is as yet neither evidence nor recommendation for their use in the setting of ST-elevated acute myocardial infarction (STEMI) treated without angioplasty.1 Their arguments about predischarge revascularisation constitute a clear sophism, which tendentiously ignores the well-proven import of early mechanical repair of the infarctrelated artery.2 Similarly, the example of prophylactic appendectomy is as rhetorical as it is wrong. One could stretch Bogaty and Brophy’s example to the absurd extent that randomised trials to compare primary angioplasty and thrombolysis2 should consider primary angioplasty an adverse event. Nonetheless, we maintain that we have not compared specific treatments but rather two different strategies for patients with heart attack (the equivalent to diagnosed acute appendicitis, in Bogaty and Brophy’s example). With this point in mind, early anatomy-based revascularisation constituted the essence of the invasive strategy, whereas predischarge ischaemia-driven revascularisation was seen as an inseparable part of the so-called ischaemia-guided conservative strategy. Both approaches had to be completed in every patient before their effect in preventing further events could be compared, and we established discharge as the moment from which the components of the primary endpoint had to be counted. Therefore, we analysed predischarge ischaemiadriven revascularisation in the conservative group as a secondary endpoint, but did not consider it as part of the primary endpoint. No patient in the invasive-treatment group needed planned ischaemiadriven revascularisation before dis-
charge. By contrast, 21 patients in the conservative-treatment group underwent predischarge planned revascularisation due to stressinduced ischaemia (8% vs 0%, p0·001). Most importantly, conservative patients had more in-hospital unplanned revascularisations induced by spontaneous ischaemia (12% vs 2%, relative risk 0·20, 95% CI 0·09–0·48, p0·001). Therefore, if we had included in the primary endpoint ischaemia-driven revascularisations done before discharge, the incidence of the primary endpoint at 1 year would have been 9% in the invasive group and 41% in the conservative group (relative risk 0·15, 0·08–0·24, p0·001), representing a risk reduction of 85% in favour of the interventional group, which is clearly higher than we observed with our design. The early post-thrombolysis interventional approach safely allows risk stratification, shortens hospital stay, and seems to improve outcome. Consequently, to think that this strategy might be preferable to a conservative one is reasonable. Furthermore, this approach reduces early recurrence of spontaneous ischaemic events. This beneficial effect on such an ominous complication coincides with the meta-analysis by Gibson3 on the outcome of 20 101 patients with thrombolysed STEMI, the results of which show that early post-thrombolysis reinfarction is associated with increased mortality up to 2 years and that early routine intervention reduces both risk of early reinfarction and 2-year mortality. Finally, the GRACIA strategy can be safely applied in hospitals without a cath-lab in coordination with tertiary centres. Thus, the approach might represent an acceptable alternative for the still high proportion of patients with STEMI for whom the gold standard of care (primary angioplasty) is not available for logistical reasons.4 This scenario makes sense even from a public-payer perspective.
We declare that we have no conflict of interest.
*Francisco Fernández-Avilés, Pedro L Sánchez, on behalf of the GRACIA Group [email protected] Insitituto de Ciencias del Corazón (ICICOR), University Hospital, School of Medicine, Valladolid, Spain 1
2
3
4
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary. Circulation 2004; 110: 588–636. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13–20. Gibson CM, Karha J, Murphy SA, et al. Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis In Myocardial Infarction Trials. J Am Coll Cardiol 2003; 42: 7–16. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin: the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23: 1190–201.
Sickle-cell disease and the patient Marie Stuart and Ronald Nagel’s Seminar (Oct 9, p 1343)1 and Michaela Buckner’s Personal Account (p 1361)2 highlight the differences between sickle-cell disease and the patient. Michaela need not worry about the disease being “a systemic disorder of monumental complexity”,1 because the patient is far from complex. Three of my siblings had sickle-cell disease (chwechweechwe),3 which can be traced back in my family to 1670 (family tree available at http://www. sicklecell.md/images/generation.jpg). Stuart and Nagel missed something out of their Seminar, which Michaela emphasises—circumstances. “The dreaded malaria” and “wearing [. . . ] traditional African clothes in December in the UK”2 that Michaela describes are known causes of sicklecell crises.3–5 A child I treated who was homozygous for the disease had a www.thelancet.com Vol 365 January 29, 2005
Correspondence
www.thelancet.com Vol 365 January 29, 2005
Work on transgenic mice might answer some of the questions about sickle-cell disease, but will probably never be able to explain why one of my patients went into severe crisis on hearing that his mother had died.3 I declare that I have no conflict of interest.
Felix I D Konotey-Ahulu [email protected] Department of Tropical Medicine, Cromwell Hospital, London SW5 0TU, UK 1 2
3
4
5
Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004; 364: 1343–60. Buckner M. Sickle-cell disease: from Sierra Leone to southeast London. Lancet 2004; 364: 1361. Konotey-Ahulu FID. The sickle cell disease patient: natural history from a clinicoepidemiological study of the first 1550 patients of Korle Bu Hospital Sickle Cell Clinic. Watford: Tetteh-A’Domeno, 1996. Konotey-Ahulu FID. The sickle cell diseases: clinical manifestations including the “Sickle Crisis”. Arch Intern Med 1974; 133: 611–19. Konotey-Ahulu FID. Effect of environment on sickle cell disease in West Africa: epidemiologic and clinical considerations. In: Abramson H, Bertles JF, Wethers DL, eds. Sickle cell disease, diagnosis, management, education, and research. St Louis: The C V Mosby Company, 1973: 20–38.
within the eligible cohort seems to be about 15% lower in the intervention areas (2972/14 8881000=199·7) than in control areas (3303/14 047 1000=235·1). Such a difference in fertility might also imply differences in birth interval, either related to preexisting differences between the intervention and control areas or to the intervention itself, by enhancing demand or improving existing family planning services. The 2001 DHS for Nepal noted that 60% of birth intervals were less than 3 years, and 23% were less than 2 years.3 Although contraceptive prevalence was 39% nationally in 2001, unmet need for family planning was still 16% for limiting births and 11% for spacing. Although birth spacing cannot account for the large difference in neonatal mortality seen in the Manandhar study, it could have contributed substantially. In any case, to be credible, studies on the effect of child survival interventions should take the important effect of birth interval into account. I declare that I have no conflict of interest.
Birth spacing and neonatal mortality Manandhar and colleagues’ article (Sept 11, p 970)1 on the effect of women’s groups in Nepal represents progress in the challenge to reduce neonatal mortality in the developing world. Surprisingly, however, birth spacing is not addressed. Birth spacing is increasingly recognised as a major determinant of various infant health indicators, including neonatal mortality. Analysis of Demographic and Health Surveys (DHS) from around the developing world, controlling for various potential confounders, indicates neonatal mortality is reduced by roughly 40% for preceding birth intervals of 3 years or more, compared with intervals of less than 2 years.2 Manandhar and colleagues’ data suggest important fertility differences between their intervention and control areas. Notably, the general fertility rate
James D Shelton [email protected] Bureau for Global Health, Agency for International Development, Washington, DC 2523, USA 1
2
3
Manandhar DS, Osrin D, Shrestha BP, et al. Effect of a participatory intervention with women’s groups on birth outcomes in Nepal: cluster-randomised controlled trial. Lancet 2004; 364: 970–79. Setty-Venugopal V, Upadhyay UD. Birth spacing: three to five saves lives. Baltimore: Johns Hopkins University, Population Information Program, 2002. Ministry of Health, Nepal, New Era, and ORC Macro. Nepal demographic and health survey 2001. Kathmandu: Calverton, 2002.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Authors’ reply James Shelton raises three important points about short birth intervals and neonatal mortality in developing countries. First, he points out the increased neonatal mortality associated with short birth intervals. In the Makwanpur trial the neonatal mortality rate was 42 per 1000 (43/1030 livebirths; 95% CI 29–54) in mothers 383
Panos Pictures
stroke because his grandmother took him out without an overcoat; his identical twin, who stayed at home, was not saved by cation homoeostasis1 or variations in vascular cell adhesion molecule-1 (VCAM-1) bonding to the endothelium via 41. My ancestors3 knew the difference between “gbagblaa” (SS-phenotype) and “pi-gbagblaa”, SC-phenotype,4 and made sure that survival was optimised through the rigourous observation of specific circumstances .3–5 One in 16 women with an increased rate of urinary tract infections in pregnancy and one in four men, is homozygous and hemizygous, respectively, for glucouse 6-phosphate dehydrogenase (G6PD) deficiency,3–5 jeopardising antimicrobial therapy.5 If Michaela Buckner is homozygous for G6PD deficiency, then both her children will be hemizygous; if heterozygous, the son with the more severe disease could well be the one carrying her G6PD-deficient gene.5 By keeping a detailed diary, she should soon find what tips them into crisis. She should try to meet patients with sickle-cell disease who manage without hydroxyurea and diamorphine or morphine for crisis pain and ask them how. Clinicians should assess new presenting symptoms, such as gnathopathy,3–5 the numb lower lip,3,4 and accelerated finger clubbing,3 and seek information about how patients are treating themselves. When a patient who is able to manage their disease without drugs claims that a nutrient like aerobic oxygen has kept them symptom-free for decades, doctors should pay attention. Antibiotics, folic acid, pneumovaccine, plenty of water, a good community nurse, family doctors that listen, together with strict attention to circumstances, will help keep Michaela’s boys out of hospital. She should teach them that half their children will have sickle-cell disease if they marry someone with the trait, which one in three west Africans carries.3–5