Risk Score for Predicting Death in Chagas' Heart Disease
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Rassi et al. (Aug. 24 issue)1 developed a risk score to predict death in Chagas' disease. They used data obtained by clinical examination and routine noninvasive tests. We analyzed our own data in order to evaluate the performance of the risk score in an independent sample. In a cohort of 183 patients with Chagas' disease and without other cardiopathies or diseases, we followed 158 patients for 5 years or more at the Federal University of Minas Gerais, in Belo Horizonte, Brazil. All patients were evaluated by means of clinical examination, electrocardiography, chest radiography, echocardiography, Holter monitoring, and exercise testing. They were classified (according to the risk score) as low-, intermediate-, or high-risk patients, and their vital status at 5 years was assessed. Although our cohort differs from that of Rassi et al., including a smaller proportion of high-risk patients, the observed 5-year risk of death for each risk stratum in the two cohorts was similar (Table 1). The score that Rassi et al. developed was a powerful predictive tool in our sample and may be valuable in clinical practice for stratifying the risk of death among patients with Chagas' disease.
Table 1. Risk of Death at 5 Years in the Original and External Cohorts According to the Risk Categories of Rassi et al. for Patients with Chagas' Disease.
Manoel O.C. Rocha, M.D., Ph.D.
Antonio L. Ribeiro, M.D., Ph.D.
Universidade Federal de Minas Gerais
30130-100 Belo Horizonte, Brazil
tom@hc.ufmg.br
References
Rassi A Jr, Rassi A, Little WC, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med 2006;355:799-808.
To the Editor: In the study by Rassi et al., the percentage of patients treated with amiodarone was high, whereas the percentage treated with angiotensin-converting–enzyme (ACE) inhibitors or beta-blockers was low. ACE inhibitors have a known effect on the prognosis of these patients. Furthermore, the exclusion of patients over 70 years of age who had sustained ventricular tachycardia or pacemakers is not justified, in our opinion, for the predictive analysis of the risk of death. Finally, the multivariate analysis excluded some measures of left ventricular function derived from the echocardiogram. Only one such variable, segmental or global wall-motion abnormality, was included. Systolic function is an important predictor of the risk of death, as illustrated in a previous score of risk derived from a cohort of 856 patients.1 The results of the Cox model and the score could have changed substantially with the inclusion of left ventricular ejection fraction or other measures of systolic function.2
Rodolfo Viotti, M.D.
Carlos Vigliano, M.D.
Alejandro Armenti, M.D.
Hospital Eva Perón
1650 Buenos Aires, Argentina
peron@millicom.com.ar
References
Viotti R, Vigliano C, Lococo B, et al. Clinical predictors of chronic chagasic myocarditis progression. Rev Esp Cardiol 2005;58:1037-1044.
Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models. Ann Intern Med 1993;118:201-210.
To the Editor: In the article by Rassi et al. concerning Chagas' cardiomyopathy, we were particularly intrigued by the finding that low voltage on the electrocardiogram was an independent risk factor for death. We recently reported an association between low electrocardiographic voltage and adverse outcomes in patients with systolic heart failure.1 In our experience, low electrocardiographic voltage was associated with a reduced ratio of left ventricular mass to body-surface area. We would be interested in knowing whether low electrocardiographic voltage was associated with a similar cardiac phenotype in patients with Chagas' cardiomyopathy.
Sandeep A. Kamath, M.D.
Mark H. Drazner, M.D., M.Sc.
University of Texas Southwestern Medical Center
Dallas, TX 75390
References
Kamath SA, Meo Neto Jde P, Canham RM, et al. Low voltage on the electrocardiogram is a marker of disease severity and a risk factor for adverse outcomes in patients with heart failure due to systolic dysfunction. Am Heart J 2006;152:355-361.
To the Editor: Chagas' disease is too often neglected in developed countries, as noted by Maguire in his recent Perspective article.1 DNA vaccines able to prevent Trypanosoma cruzi infection in animal models have been repeatedly created in the past decade, based on highly conserved amastigote or trypomastigote antigens.2,3 However, in searching PubMed for publications on clinical trials for Chagas' disease, my colleagues and I were astonished by the lack of any trials of preventive vaccination.4
Aside from vector control and the screening of blood donors, vaccination is a very effective strategy for reducing costs associated with health care, especially in developing countries. When dealing with life-threatening complications from such a well-defined infectious disease, I believe that more money should be focused on prevention rather than on treatments that have low therapeutic indexes (e.g., most antiprotozoal medications) or very high cost (e.g., heart transplantation). What's more, therapeutic vaccines (i.e., those administered during the chronic phase of Chagas' disease) have been shown to reduce the severity of cardiomyopathy in infected animal models.5 When will the time come for a field trial?
Daniele Focosi, M.D.
Azienda Ospedaliera Universitaria Santa Chiara
56100 Pisa, Italy
focosi@icgeb.org
References
Maguire JH. Chagas' disease -- can we stop the deaths? N Engl J Med 2006;355:760-761.
Boscardin SB, Kinoshita SS, Fujimura AE, Rodrigues MM. Immunization with cDNA expressed by amastigotes of Trypanosoma cruzi elicits protective immune response against experimental infection. Infect Immun 2003;71:2744-2757.
Sepulveda P, Hontebeyrie M, Liegeard P, Mascilli A, Norris KA. DNA-based immunization with Trypanosoma cruzi complement regulatory protein elicits complement lytic antibodies and confers protection against Trypanosoma cruzi infection. Infect Immun 2000;68:4986-4991.
PubMed search for "Chagas disease vaccine" using the "My NCBI" Clinical Trial filter. (Accessed November 17, 2006, at http://www.ncbi.nlm.nih.gov/entrez/login.fcgi.)
Zapata-Estrella A, Hummel-Newell C, Sanchez-Burgos G, et al. Control of Trypanosoma cruzi infection and changes in T-cell populations induced by a therapeutic DNA vaccine in mice. Immunol Lett 2006;103:186-191.
Dr. Rassi and colleagues reply: The observation and the contribution of Drs. Rocha and Ribeiro confirm the accuracy of our clinical risk score in predicting death in Chagas' heart disease in another independent cohort. Dr. Viotti and colleagues are concerned that amiodarone was frequently administered to our study population (the development cohort), whereas ACE inhibitors and beta-blockers were not. The high use of amiodarone can be explained by the presence of palpitations in 30% of our patients and by the frequent occurrence of episodes of nonsustained ventricular tachycardia (46.5%). Regarding the low use of ACE inhibitors and beta-blockers, it should be noted that our study started in 1986 and was conducted before the widespread acceptance of these agents as standard therapy for patients with heart failure. Although heart failure in Chagas' disease is treated in a similar fashion to heart failure from other causes, the efficacy of ACE inhibitors and beta-blockers for reducing the risk of death in this population remains to be established.
Dr. Viotti and colleagues also question why we excluded patients older than 70 years of age and with sustained ventricular tachycardia or pacemakers at study entry. We excluded these patients before analyzing the data to avoid the effects of coexisting conditions and to prevent the inclusion of patients who were already known to have a poor prognosis1 or whose prognosis had already changed owing to a specific intervention.2
Finally, Dr. Viotti and colleagues suggest that other measures of systolic left ventricular function, such as ejection fraction, should have been included in our analysis. Echocardiographic left ventricular function and dimension were evaluated by visual interpretation in our study. In clinical practice, the visual estimation of ejection fraction from two-dimensional echocardiography is common and has been reported to yield results that correspond closely to those obtained by other sophisticated methods.3,4 Left ventricular diastolic diameter was not included in the multivariate analysis because it showed colinearity with wall-motion abnormalities and cardiomegaly.
Drs. Kamath and Drazner wonder whether low electrocardiographic voltage in Chagas' heart disease could be due to a reduced ratio of left ventricular mass to body-surface area. We believe that widespread myocardial fibrosis producing electrical silence plays a major role in the reduced electrocardiographic voltage. Although our study does not allow us to determine the mechanism, it does clearly show that reduced voltage, defined as voltage in each limb lead equal to or less than 0.5 mV, is an independent predictor of death in Chagas' heart disease.
Anis Rassi, Jr., M.D., Ph.D.
Anis Rassi, M.D.
Anis Rassi Hospital
74.110-020 Goiania, Brazil
arassijr@arh.com.br
William C. Little, M.D.
Wake Forest University School of Medicine
Winston-Salem, NC 27157-1045
References
Rassi Junior A, Gabriel Rassi A, Gabriel Rassi S, Rassi Junior L, Rassi A. Ventricular arrhythmia in Chagas disease: diagnostic, prognostic, and therapeutic features. Arq Bras Cardiol 1995;65:377-87.
Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease. Arq Bras Cardiol 2001;76:75-96.
Stamm RB, Carabello BA, Mayers DL, Martin RP. Two-dimensional echocardiographic measurement of left ventricular ejection fraction: prospective analysis of what constitutes an adequate determination. Am Heart J 1982;104:136-144.
Amico AF, Lichtenberg GS, Reisner SA, Stone CK, Schwartz RG, Meltzer RS. Superiority of visual versus computerized echocardiographic estimation of radionuclide left ventricular ejection fraction. Am Heart J 1989;118:1259-1265.
Dr. Maguire replies: Formidable technical and regulatory hurdles and the lack of a commercial market in wealthy countries have stood in the way of the development of vaccines for diseases such as Chagas' disease that affect poor people in poor countries.1,2 However, large grants from the Bill and Melinda Gates Foundation and other donors, as well as private and public partnerships of companies, governments, nonprofit entities, and international organizations, are beginning to address these obstacles.2,3 In addition, recent studies of the pathogenesis of Chagas' disease have diminished concerns that a vaccine would trigger an autoimmune reaction against the heart.4 Although the case for a vaccine to prevent T. cruzi infection is compelling, it is likely that regional initiatives in Latin America5 will succeed in interrupting vector-borne and transfusion-associated transmission before such a vaccine becomes available. Dr. Focosi correctly points out the shortcomings of current treatments, and better drugs or an effective therapeutic vaccine would indeed bring immeasurable benefit to the million or more persons already infected with T. cruzi.
James H. Maguire, M.D., M.P.H.
University of Maryland School of Medicine
Baltimore, MD 21201
References
Ehrenberg JP, Ault SK. Neglected diseases of neglected populations: thinking to reshape the determinants of health in Latin America and the Caribbean. BMC Public Health 2005;5:119-119.
Clemens J, Jodar L. Introducing new vaccines into developing countries: obstacles, opportunities and complexities. Nat Med 2005;11:Suppl:S12-S15.
Mandelbaum-Schmid J. New generation of non-profit initiatives tackles world's "neglected" diseases. Bull World Health Organ 2004;82:395-396.
Zhang L, Tarleton RL. Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. J Infect Dis 1999;180:480-486.
Dias JCP, Silveira AC, Schofield CJ. The impact of Chagas disease control in Latin America: a review. Mem Inst Oswaldo Cruz 2002;97:603-612.
Table 1. Risk of Death at 5 Years in the Original and External Cohorts According to the Risk Categories of Rassi et al. for Patients with Chagas' Disease.
Manoel O.C. Rocha, M.D., Ph.D.
Antonio L. Ribeiro, M.D., Ph.D.
Universidade Federal de Minas Gerais
30130-100 Belo Horizonte, Brazil
tom@hc.ufmg.br
References
Rassi A Jr, Rassi A, Little WC, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med 2006;355:799-808.
To the Editor: In the study by Rassi et al., the percentage of patients treated with amiodarone was high, whereas the percentage treated with angiotensin-converting–enzyme (ACE) inhibitors or beta-blockers was low. ACE inhibitors have a known effect on the prognosis of these patients. Furthermore, the exclusion of patients over 70 years of age who had sustained ventricular tachycardia or pacemakers is not justified, in our opinion, for the predictive analysis of the risk of death. Finally, the multivariate analysis excluded some measures of left ventricular function derived from the echocardiogram. Only one such variable, segmental or global wall-motion abnormality, was included. Systolic function is an important predictor of the risk of death, as illustrated in a previous score of risk derived from a cohort of 856 patients.1 The results of the Cox model and the score could have changed substantially with the inclusion of left ventricular ejection fraction or other measures of systolic function.2
Rodolfo Viotti, M.D.
Carlos Vigliano, M.D.
Alejandro Armenti, M.D.
Hospital Eva Perón
1650 Buenos Aires, Argentina
peron@millicom.com.ar
References
Viotti R, Vigliano C, Lococo B, et al. Clinical predictors of chronic chagasic myocarditis progression. Rev Esp Cardiol 2005;58:1037-1044.
Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models. Ann Intern Med 1993;118:201-210.
To the Editor: In the article by Rassi et al. concerning Chagas' cardiomyopathy, we were particularly intrigued by the finding that low voltage on the electrocardiogram was an independent risk factor for death. We recently reported an association between low electrocardiographic voltage and adverse outcomes in patients with systolic heart failure.1 In our experience, low electrocardiographic voltage was associated with a reduced ratio of left ventricular mass to body-surface area. We would be interested in knowing whether low electrocardiographic voltage was associated with a similar cardiac phenotype in patients with Chagas' cardiomyopathy.
Sandeep A. Kamath, M.D.
Mark H. Drazner, M.D., M.Sc.
University of Texas Southwestern Medical Center
Dallas, TX 75390
References
Kamath SA, Meo Neto Jde P, Canham RM, et al. Low voltage on the electrocardiogram is a marker of disease severity and a risk factor for adverse outcomes in patients with heart failure due to systolic dysfunction. Am Heart J 2006;152:355-361.
To the Editor: Chagas' disease is too often neglected in developed countries, as noted by Maguire in his recent Perspective article.1 DNA vaccines able to prevent Trypanosoma cruzi infection in animal models have been repeatedly created in the past decade, based on highly conserved amastigote or trypomastigote antigens.2,3 However, in searching PubMed for publications on clinical trials for Chagas' disease, my colleagues and I were astonished by the lack of any trials of preventive vaccination.4
Aside from vector control and the screening of blood donors, vaccination is a very effective strategy for reducing costs associated with health care, especially in developing countries. When dealing with life-threatening complications from such a well-defined infectious disease, I believe that more money should be focused on prevention rather than on treatments that have low therapeutic indexes (e.g., most antiprotozoal medications) or very high cost (e.g., heart transplantation). What's more, therapeutic vaccines (i.e., those administered during the chronic phase of Chagas' disease) have been shown to reduce the severity of cardiomyopathy in infected animal models.5 When will the time come for a field trial?
Daniele Focosi, M.D.
Azienda Ospedaliera Universitaria Santa Chiara
56100 Pisa, Italy
focosi@icgeb.org
References
Maguire JH. Chagas' disease -- can we stop the deaths? N Engl J Med 2006;355:760-761.
Boscardin SB, Kinoshita SS, Fujimura AE, Rodrigues MM. Immunization with cDNA expressed by amastigotes of Trypanosoma cruzi elicits protective immune response against experimental infection. Infect Immun 2003;71:2744-2757.
Sepulveda P, Hontebeyrie M, Liegeard P, Mascilli A, Norris KA. DNA-based immunization with Trypanosoma cruzi complement regulatory protein elicits complement lytic antibodies and confers protection against Trypanosoma cruzi infection. Infect Immun 2000;68:4986-4991.
PubMed search for "Chagas disease vaccine" using the "My NCBI" Clinical Trial filter. (Accessed November 17, 2006, at http://www.ncbi.nlm.nih.gov/entrez/login.fcgi.)
Zapata-Estrella A, Hummel-Newell C, Sanchez-Burgos G, et al. Control of Trypanosoma cruzi infection and changes in T-cell populations induced by a therapeutic DNA vaccine in mice. Immunol Lett 2006;103:186-191.
Dr. Rassi and colleagues reply: The observation and the contribution of Drs. Rocha and Ribeiro confirm the accuracy of our clinical risk score in predicting death in Chagas' heart disease in another independent cohort. Dr. Viotti and colleagues are concerned that amiodarone was frequently administered to our study population (the development cohort), whereas ACE inhibitors and beta-blockers were not. The high use of amiodarone can be explained by the presence of palpitations in 30% of our patients and by the frequent occurrence of episodes of nonsustained ventricular tachycardia (46.5%). Regarding the low use of ACE inhibitors and beta-blockers, it should be noted that our study started in 1986 and was conducted before the widespread acceptance of these agents as standard therapy for patients with heart failure. Although heart failure in Chagas' disease is treated in a similar fashion to heart failure from other causes, the efficacy of ACE inhibitors and beta-blockers for reducing the risk of death in this population remains to be established.
Dr. Viotti and colleagues also question why we excluded patients older than 70 years of age and with sustained ventricular tachycardia or pacemakers at study entry. We excluded these patients before analyzing the data to avoid the effects of coexisting conditions and to prevent the inclusion of patients who were already known to have a poor prognosis1 or whose prognosis had already changed owing to a specific intervention.2
Finally, Dr. Viotti and colleagues suggest that other measures of systolic left ventricular function, such as ejection fraction, should have been included in our analysis. Echocardiographic left ventricular function and dimension were evaluated by visual interpretation in our study. In clinical practice, the visual estimation of ejection fraction from two-dimensional echocardiography is common and has been reported to yield results that correspond closely to those obtained by other sophisticated methods.3,4 Left ventricular diastolic diameter was not included in the multivariate analysis because it showed colinearity with wall-motion abnormalities and cardiomegaly.
Drs. Kamath and Drazner wonder whether low electrocardiographic voltage in Chagas' heart disease could be due to a reduced ratio of left ventricular mass to body-surface area. We believe that widespread myocardial fibrosis producing electrical silence plays a major role in the reduced electrocardiographic voltage. Although our study does not allow us to determine the mechanism, it does clearly show that reduced voltage, defined as voltage in each limb lead equal to or less than 0.5 mV, is an independent predictor of death in Chagas' heart disease.
Anis Rassi, Jr., M.D., Ph.D.
Anis Rassi, M.D.
Anis Rassi Hospital
74.110-020 Goiania, Brazil
arassijr@arh.com.br
William C. Little, M.D.
Wake Forest University School of Medicine
Winston-Salem, NC 27157-1045
References
Rassi Junior A, Gabriel Rassi A, Gabriel Rassi S, Rassi Junior L, Rassi A. Ventricular arrhythmia in Chagas disease: diagnostic, prognostic, and therapeutic features. Arq Bras Cardiol 1995;65:377-87.
Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease. Arq Bras Cardiol 2001;76:75-96.
Stamm RB, Carabello BA, Mayers DL, Martin RP. Two-dimensional echocardiographic measurement of left ventricular ejection fraction: prospective analysis of what constitutes an adequate determination. Am Heart J 1982;104:136-144.
Amico AF, Lichtenberg GS, Reisner SA, Stone CK, Schwartz RG, Meltzer RS. Superiority of visual versus computerized echocardiographic estimation of radionuclide left ventricular ejection fraction. Am Heart J 1989;118:1259-1265.
Dr. Maguire replies: Formidable technical and regulatory hurdles and the lack of a commercial market in wealthy countries have stood in the way of the development of vaccines for diseases such as Chagas' disease that affect poor people in poor countries.1,2 However, large grants from the Bill and Melinda Gates Foundation and other donors, as well as private and public partnerships of companies, governments, nonprofit entities, and international organizations, are beginning to address these obstacles.2,3 In addition, recent studies of the pathogenesis of Chagas' disease have diminished concerns that a vaccine would trigger an autoimmune reaction against the heart.4 Although the case for a vaccine to prevent T. cruzi infection is compelling, it is likely that regional initiatives in Latin America5 will succeed in interrupting vector-borne and transfusion-associated transmission before such a vaccine becomes available. Dr. Focosi correctly points out the shortcomings of current treatments, and better drugs or an effective therapeutic vaccine would indeed bring immeasurable benefit to the million or more persons already infected with T. cruzi.
James H. Maguire, M.D., M.P.H.
University of Maryland School of Medicine
Baltimore, MD 21201
References
Ehrenberg JP, Ault SK. Neglected diseases of neglected populations: thinking to reshape the determinants of health in Latin America and the Caribbean. BMC Public Health 2005;5:119-119.
Clemens J, Jodar L. Introducing new vaccines into developing countries: obstacles, opportunities and complexities. Nat Med 2005;11:Suppl:S12-S15.
Mandelbaum-Schmid J. New generation of non-profit initiatives tackles world's "neglected" diseases. Bull World Health Organ 2004;82:395-396.
Zhang L, Tarleton RL. Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. J Infect Dis 1999;180:480-486.
Dias JCP, Silveira AC, Schofield CJ. The impact of Chagas disease control in Latin America: a review. Mem Inst Oswaldo Cruz 2002;97:603-612.