- Email: [email protected]
Might losartan reduce sudden cardiac death in diabetic patients with hypertension?
COMMENTARY
Spierings and colleagues’ findings have direct clinical consequences. Donor-recipient sex combination should now be considered in any organ-allocation or donorselection algorithm. For a solid-organ transplant, the decision is fairly simple: when choice is possible, HLAidentical organs should be allocated to sex-matched recipients. The decision is more complex for haemopoietic stem-cell transplantation; both rejection and graft-versus-host disease have to be considered. Rejection is more of a risk when males donate to female recipients, graft-versus-host disease more important when females donate to males. Rejection is primarily of concern when transplantation has been done for aplastic anaemia or congenital haemoglobinopathies. For these indications, if choice can be made, a male donor for a female recipient should be avoided. The situation is even more complex in haematological malignancies, in which transplant-related mortality is more of a problem than rejection. The risk of transplantrelated mortality due to graft-versus-host disease is higher for males with female donors, and some strategies advocate avoiding female donors for male recipients. This decision might need to be reconsidered, as H-Yderived peptides are not only recognised on normal tissue as a basis for a graft-versus-host response, but can also trigger a graft-versus-tumour response. Indeed, disease relapse is lower in male recipients of female allografts.9,10 However, in the short term, survival is still worse for males with female grafts—ie, the detrimental effect of graft-versus-host reaction is higher than the benefit from graft-versus-leukaemia effect; so, if possible, sex-matched donors should continue to be chosen for male recipients. If, with longer follow-up, the graft-versus-leukaemia benefit outweighs early loss, survival curves might cross, and it will be necessary to reconsider the decisions of today. These findings raise intriguing questions. They do not explain why females recognise male gene products. Even less do they explain why the anti-Y response remains a rare event. Why are so many HLA-identical sexmismatched transplants accepted with no rejection? Why are male fetuses as safe during pregnancy as female ones? The cases we observe might simply be accidents of nature. For example, the RPS4Y peptide, as described by Spierings and colleagues, differs in two aminoacids from the RPS4X peptide.11 It is unknown whether the difference in this peptide, a ribosomal protein, represents a spontaneous mutation or reflects a more common mutation with more widespread implications. I have no conflict of interest to declare.
A Gratwohl
2 3
4
5
Wang W, Meadows LR, den Haan JM, et al. Human H-Y: a malespecific histocompatibility antigen derived from the SMCY protein. Science 1995; 269: 1588–90. 7 Zwaan FE, Hermans J, Gratwohl A, for the EBMT Leukaemia Party (EBMT-LWP). The influence of donor-recipient sex mismatching on the outcome of allogeneic BMT in leukemia. Bone Marrow Transplant 1989; 4 (suppl 2): 8. 8 Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation: Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998; 352: 1087–92. 9 Gratwohl A, Hermans J, Niederwieser D, van Biezen A, van Houwelingen HC, Apperley J. Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematolol J 2001; 2: 363–70. 10 Randolph SB, Warren EH, Riddell SR. Identification of novel minor histocompatibility antigens encoded by the Y chromosome gene, UTY. American Society of Hematology, 44th Annual Meeting Program, December, 2002: abstr. 11 Bergen AW, Pratt M, Mehlman PT, Goldman D. Evolution of RPS4Y. Mol Biol Evol 1998; 15: 1412–19.
Might losartan reduce sudden cardiac death in diabetic patients with hypertension? See page 619 In today’s Lancet, Lars Lindholm and colleagues report on a subgroup of diabetic patients with left ventricular hypertrophy from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Data from the diabetic subgroup in the LIFE study1 showing a 37% significant reduction in cardiovascular mortality and a 39% significant reduction in all-cause mortality by losartan compared with atenolol led the investigators to do a posthoc analysis of sudden cardiac death in this population. Their new analysis shows that losartan-based antihypertensive therapy significantly prevents sudden cardiac death better than atenolol-based antihypertensive therapy. The investigators suggest that the results are related to a better protection against cardiac death from arrhythmias by losartan compared with atenolol. They state that their analyses are exploratory and require confirmation. The data from the LIFE trial clearly show the superiority of losartan to atenolol in the treatment of hypertensive diabetic patients with left ventricular hypertrophy. However, can these data be extrapolated to treatment with blockers, other than atenolol, that have been shown to reduce sudden cardiac death? Controlled clinical trials show that blockers, such as propranolol, timolol, metoprolol, and carvedilol, significantly reduce sudden cardiac death in postinfarction patients,2 4 in high-risk survivors of acute myocardial infarction,5 in patients with congestive heart failure,6,7 and in patients with complex ventricular arrhythmias associated with previous myocardial infarction8,9 or hypertensive heart disease9 and a left ventricular ejection fraction 40%8 or 40%9 (table). The reduction in sudden cardiac death in elderly patients with previous myocardial infarction or hypertensive heart disease and complex ventricular arrhythmias after propranolol was due more to an anti-ischaemic effect than to an antiarrhythmic effect.10 Propranolol also abolished the circadian variation of sudden cardiac death or fatal myocardial infarction.11 However, no reduction in sudden cardiac death occurs with the hydrophilic blocker, atenolol. By increasing levels of cardiac vagal tone and electrical stability in the heart, -receptor blockade in the brain might contribute to the reduction in sudden cardiac death seen with lipophilic blockers.12 -
Haematology and Stem Cell Transplantation Unit, University of Basel, CH-4031 Basel, Switzerland (e-mail: [email protected]) 1
6
Uphoff DE. Comparative survival of lethally irradiated inbred male mice inoculated with marrow from virgin or multiparous female donors. J Natl Cancer Inst 1975; 54: 1343–47. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Alloimmunity to human H-Y. Lancet 1976; 2: 1206. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Y-antigen killing by T cells of women is restricted by HLA. Nature 1977; 26: 544–45. Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–85. Rufer N, Wolpert E, Helg C, et al. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation 1998; 66: 910–16.
THE LANCET • Vol 362 • August 23, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
591
COMMENTARY
Effect of blockers on sudden cardiac death Study
Results
Beta Blocker Versus placebo, propranolol significantly Heart Attack Trial2 reduced sudden cardiac death by 28% in postinfarction patients Norwegian Versus placebo, timolol significantly Multicentre Study reduced sudden cardiac death by 40% in postinfarction patients Group Trial3 Pooled analysis Versus placebo, metoprolol significantly from five trials4 reduced sudden cardiac death by 41% in postinfarction patients Norwegian Versus placebo, propranolol significantly Propranolol Study5 reduced sudden cardiac death by 52% in high-risk survivors of acute myocardial infarction US Carvedilol Versus placebo, carvedilol significantly Heart Failure Study6 reduced sudden cardiac death by 55% in patients with heart failure Metoprolol CR/XL Versus placebo, metoprolol significantly Randomised reduced sudden cardiac death by 41% in Intervention Trial patients with heart failure in Congestive Heart Failure (MERIT-HF)7 Cardiac Arrhythmia In postinfarction patients with complex Suppression Trial8 ventricular arrhythmias and left ventricular ejection fraction 40%, use of blockers was significant independent factor for reducing sudden cardiac death by 40% Aronow et al9 In elderly patients with previous myocardial infarction (64%) or hypertensive heart disease (36%), complex ventricular arrhythmias, and left ventricular ejection fraction 40%, patients randomised to propranolol had 47% significant reduction in sudden cardiac death
In a randomised primary prevention trial of men with hypertension, metoprolol, compared with a thiazide diuretic, significantly reduced sudden cardiac death by 30%.13 By contrast, the UK Medical Research Council primary prevention trial of treatment of hypertension in older patients showed that atenolol did not reduce coronary events compared with placebo.14 Coope and Warrender15 also showed that atenolol did not reduce coronary events in older hypertensive patients. Lindholm and colleagues’ new analysis, and their previous report,1 showing a significant reduction in cardiovascular mortality and in all-cause mortality by losartan compared with atenolol show that losartan is more effective than atenolol in treating hypertensive diabetic patients with left ventricular hypertrophy. However, a large double-blind randomised trial is necessary to investigate whether losartan is better, similar, or worse than propranolol, timolol, metoprolol, or carvedilol in reducing sudden cardiac death and coronary events. Complex ventricular arrhythmias contribute to a higher incidence of sudden cardiac death in hypertensive patients with left ventricular hypertrophy.16,17 Left ventricular hypertrophy increases the occurrence of atrial fibrillation,18 and atrial fibrillation is associated with increased cardiovascular mortality after controlling for other prognostic variables.19,20 Therefore a double-blind trial investigating the incidence of sudden cardiac death in diabetic patients with left ventricular hypertrophy randomised to losartan versus a blocker (such as 592
propranolol, timolol, metoprolol, or carvedilol) should stratify by risk before randomisation for complex ventricular arrhythmias, atrial fibrillation, and leftventricular ejection fraction. I have no conflict of interest to declare.
Wilbert S Aronow Department of Medicine, Divisions of Cardiology and Geriatrics, Westchester Medical Center and New York Medical College, Valhalla, NY 10595, USA (e-mail: [email protected]) 1
2
3
4
5
6
7
8
9
10
11
12 13
14
15
16
17
18
19
20
Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. JAMA 1982; 247: 1707–14. Gundersen T, Abrahamsen AM, Kjekshus J, for the Norwegian Multicentre Study Group. Timolol-related reduction in mortality and reinfarction in patients ages 65–75 years surviving acute myocardial infarction. Circulation 1982; 66: 1179–84. Olsson G, Wikstrand J, Warnold I, et al. Metoprolol-induced reduction in postinfarction mortality: results from five double-blind randomized trials. Eur Heart J 1992; 11: 28–32. Hansteen V. Beta blockade after myocardial infarction: the Norwegian Propranolol Study in high-risk patients. Circulation 1983; 67 (suppl I): I-57–I-60. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–07. Kennedy HL, Brooks MM, Barker AH, et al. Beta-blocker therapy in the Cardiac Arrhythmia Suppression Trial. Am J Cardiol 1994; 74: 674–80. Aronow WS, Ahn C, Mercando AD, Epstein S, Kronzon I. Effect of propranolol versus no antiarrhythmic drug on sudden cardiac death, total cardiac death, and total death in patients 62 years of age with heart disease, complex ventricular arrhythmias, and left ventricular ejection fraction 40%. Am J Cardiol 1994; 74: 267–70. Aronow WS, Ahn C, Mercando AD, Epstein S., Kronzon I. Decrease of mortality by propranolol in patients with heart disease and complex ventricular arrhythmias is more an anti-ischemic than an antiarrhythmic effect. Am J Cardiol 1994; 74: 613–15. Aronow WS, Ahn C, Mercando AD, Epstein S. Circadian variation of sudden cardiac death or fatal myocardial infarction is abolished by propranolol in patients with heart disease and complex ventricular arrhythmias. Am J Cardiol 1994; 74: 819–21. Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden death. Eur Heart J 1992; 12 (suppl D): 111–20. Olsson G, Tuomilehto J, Berglund G, et al. Primary prevention of sudden cardiovascular death in hypertensive patients: mortality results from the MAPHY Study. Am J Hypertens 1991; 4: 151–58. MRC Working Party. Medical Research Council Trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Coope J, Warrender TS. Randomised trial of the treatment of hypertension in elderly patients in primary care. BMJ 1986; 293: 1145–51. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984; 77: 18–22. Aronow WS, Epstein SE, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic left ventricular hypertrophy, ventricular tachycardia and complex ventricular arrhythmias in predicting ventricular fibrillation or sudden cardiac death in elderly patients. Am J Cardiol 1988; 62: 1124–25. Aronow WS, Ahn C, Kronzon I, Gutstein H. Association of left ventricular hypertrophy and chronic atrial fibrillation with the incidence of new thromboembolic stroke in 2,384 older persons. Am J Cardiol 1999; 84: 468–69. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–52. Aronow WS, Ahn C, Mercando AD, Epstein S. Correlation of atrial fibrillation, paroxysmal supraventricular tachycardia, and sinus rhythm with incidences of new coronary events in 1,359 patients, mean age 81 years, with heart disease. Am J Cardiol 1995; 75: 182–84.
THE LANCET • Vol 362 • August 23, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
Spierings and colleagues’ findings have direct clinical consequences. Donor-recipient sex combination should now be considered in any organ-allocation or donorselection algorithm. For a solid-organ transplant, the decision is fairly simple: when choice is possible, HLAidentical organs should be allocated to sex-matched recipients. The decision is more complex for haemopoietic stem-cell transplantation; both rejection and graft-versus-host disease have to be considered. Rejection is more of a risk when males donate to female recipients, graft-versus-host disease more important when females donate to males. Rejection is primarily of concern when transplantation has been done for aplastic anaemia or congenital haemoglobinopathies. For these indications, if choice can be made, a male donor for a female recipient should be avoided. The situation is even more complex in haematological malignancies, in which transplant-related mortality is more of a problem than rejection. The risk of transplantrelated mortality due to graft-versus-host disease is higher for males with female donors, and some strategies advocate avoiding female donors for male recipients. This decision might need to be reconsidered, as H-Yderived peptides are not only recognised on normal tissue as a basis for a graft-versus-host response, but can also trigger a graft-versus-tumour response. Indeed, disease relapse is lower in male recipients of female allografts.9,10 However, in the short term, survival is still worse for males with female grafts—ie, the detrimental effect of graft-versus-host reaction is higher than the benefit from graft-versus-leukaemia effect; so, if possible, sex-matched donors should continue to be chosen for male recipients. If, with longer follow-up, the graft-versus-leukaemia benefit outweighs early loss, survival curves might cross, and it will be necessary to reconsider the decisions of today. These findings raise intriguing questions. They do not explain why females recognise male gene products. Even less do they explain why the anti-Y response remains a rare event. Why are so many HLA-identical sexmismatched transplants accepted with no rejection? Why are male fetuses as safe during pregnancy as female ones? The cases we observe might simply be accidents of nature. For example, the RPS4Y peptide, as described by Spierings and colleagues, differs in two aminoacids from the RPS4X peptide.11 It is unknown whether the difference in this peptide, a ribosomal protein, represents a spontaneous mutation or reflects a more common mutation with more widespread implications. I have no conflict of interest to declare.
A Gratwohl
2 3
4
5
Wang W, Meadows LR, den Haan JM, et al. Human H-Y: a malespecific histocompatibility antigen derived from the SMCY protein. Science 1995; 269: 1588–90. 7 Zwaan FE, Hermans J, Gratwohl A, for the EBMT Leukaemia Party (EBMT-LWP). The influence of donor-recipient sex mismatching on the outcome of allogeneic BMT in leukemia. Bone Marrow Transplant 1989; 4 (suppl 2): 8. 8 Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation: Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998; 352: 1087–92. 9 Gratwohl A, Hermans J, Niederwieser D, van Biezen A, van Houwelingen HC, Apperley J. Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematolol J 2001; 2: 363–70. 10 Randolph SB, Warren EH, Riddell SR. Identification of novel minor histocompatibility antigens encoded by the Y chromosome gene, UTY. American Society of Hematology, 44th Annual Meeting Program, December, 2002: abstr. 11 Bergen AW, Pratt M, Mehlman PT, Goldman D. Evolution of RPS4Y. Mol Biol Evol 1998; 15: 1412–19.
Might losartan reduce sudden cardiac death in diabetic patients with hypertension? See page 619 In today’s Lancet, Lars Lindholm and colleagues report on a subgroup of diabetic patients with left ventricular hypertrophy from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Data from the diabetic subgroup in the LIFE study1 showing a 37% significant reduction in cardiovascular mortality and a 39% significant reduction in all-cause mortality by losartan compared with atenolol led the investigators to do a posthoc analysis of sudden cardiac death in this population. Their new analysis shows that losartan-based antihypertensive therapy significantly prevents sudden cardiac death better than atenolol-based antihypertensive therapy. The investigators suggest that the results are related to a better protection against cardiac death from arrhythmias by losartan compared with atenolol. They state that their analyses are exploratory and require confirmation. The data from the LIFE trial clearly show the superiority of losartan to atenolol in the treatment of hypertensive diabetic patients with left ventricular hypertrophy. However, can these data be extrapolated to treatment with blockers, other than atenolol, that have been shown to reduce sudden cardiac death? Controlled clinical trials show that blockers, such as propranolol, timolol, metoprolol, and carvedilol, significantly reduce sudden cardiac death in postinfarction patients,2 4 in high-risk survivors of acute myocardial infarction,5 in patients with congestive heart failure,6,7 and in patients with complex ventricular arrhythmias associated with previous myocardial infarction8,9 or hypertensive heart disease9 and a left ventricular ejection fraction 40%8 or 40%9 (table). The reduction in sudden cardiac death in elderly patients with previous myocardial infarction or hypertensive heart disease and complex ventricular arrhythmias after propranolol was due more to an anti-ischaemic effect than to an antiarrhythmic effect.10 Propranolol also abolished the circadian variation of sudden cardiac death or fatal myocardial infarction.11 However, no reduction in sudden cardiac death occurs with the hydrophilic blocker, atenolol. By increasing levels of cardiac vagal tone and electrical stability in the heart, -receptor blockade in the brain might contribute to the reduction in sudden cardiac death seen with lipophilic blockers.12 -
Haematology and Stem Cell Transplantation Unit, University of Basel, CH-4031 Basel, Switzerland (e-mail: [email protected]) 1
6
Uphoff DE. Comparative survival of lethally irradiated inbred male mice inoculated with marrow from virgin or multiparous female donors. J Natl Cancer Inst 1975; 54: 1343–47. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Alloimmunity to human H-Y. Lancet 1976; 2: 1206. Goulmy E, Termijtelen A, Bradley BA, van Rood JJ. Y-antigen killing by T cells of women is restricted by HLA. Nature 1977; 26: 544–45. Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–85. Rufer N, Wolpert E, Helg C, et al. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation 1998; 66: 910–16.
THE LANCET • Vol 362 • August 23, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
591
COMMENTARY
Effect of blockers on sudden cardiac death Study
Results
Beta Blocker Versus placebo, propranolol significantly Heart Attack Trial2 reduced sudden cardiac death by 28% in postinfarction patients Norwegian Versus placebo, timolol significantly Multicentre Study reduced sudden cardiac death by 40% in postinfarction patients Group Trial3 Pooled analysis Versus placebo, metoprolol significantly from five trials4 reduced sudden cardiac death by 41% in postinfarction patients Norwegian Versus placebo, propranolol significantly Propranolol Study5 reduced sudden cardiac death by 52% in high-risk survivors of acute myocardial infarction US Carvedilol Versus placebo, carvedilol significantly Heart Failure Study6 reduced sudden cardiac death by 55% in patients with heart failure Metoprolol CR/XL Versus placebo, metoprolol significantly Randomised reduced sudden cardiac death by 41% in Intervention Trial patients with heart failure in Congestive Heart Failure (MERIT-HF)7 Cardiac Arrhythmia In postinfarction patients with complex Suppression Trial8 ventricular arrhythmias and left ventricular ejection fraction 40%, use of blockers was significant independent factor for reducing sudden cardiac death by 40% Aronow et al9 In elderly patients with previous myocardial infarction (64%) or hypertensive heart disease (36%), complex ventricular arrhythmias, and left ventricular ejection fraction 40%, patients randomised to propranolol had 47% significant reduction in sudden cardiac death
In a randomised primary prevention trial of men with hypertension, metoprolol, compared with a thiazide diuretic, significantly reduced sudden cardiac death by 30%.13 By contrast, the UK Medical Research Council primary prevention trial of treatment of hypertension in older patients showed that atenolol did not reduce coronary events compared with placebo.14 Coope and Warrender15 also showed that atenolol did not reduce coronary events in older hypertensive patients. Lindholm and colleagues’ new analysis, and their previous report,1 showing a significant reduction in cardiovascular mortality and in all-cause mortality by losartan compared with atenolol show that losartan is more effective than atenolol in treating hypertensive diabetic patients with left ventricular hypertrophy. However, a large double-blind randomised trial is necessary to investigate whether losartan is better, similar, or worse than propranolol, timolol, metoprolol, or carvedilol in reducing sudden cardiac death and coronary events. Complex ventricular arrhythmias contribute to a higher incidence of sudden cardiac death in hypertensive patients with left ventricular hypertrophy.16,17 Left ventricular hypertrophy increases the occurrence of atrial fibrillation,18 and atrial fibrillation is associated with increased cardiovascular mortality after controlling for other prognostic variables.19,20 Therefore a double-blind trial investigating the incidence of sudden cardiac death in diabetic patients with left ventricular hypertrophy randomised to losartan versus a blocker (such as 592
propranolol, timolol, metoprolol, or carvedilol) should stratify by risk before randomisation for complex ventricular arrhythmias, atrial fibrillation, and leftventricular ejection fraction. I have no conflict of interest to declare.
Wilbert S Aronow Department of Medicine, Divisions of Cardiology and Geriatrics, Westchester Medical Center and New York Medical College, Valhalla, NY 10595, USA (e-mail: [email protected]) 1
2
3
4
5
6
7
8
9
10
11
12 13
14
15
16
17
18
19
20
Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 1004–10. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. JAMA 1982; 247: 1707–14. Gundersen T, Abrahamsen AM, Kjekshus J, for the Norwegian Multicentre Study Group. Timolol-related reduction in mortality and reinfarction in patients ages 65–75 years surviving acute myocardial infarction. Circulation 1982; 66: 1179–84. Olsson G, Wikstrand J, Warnold I, et al. Metoprolol-induced reduction in postinfarction mortality: results from five double-blind randomized trials. Eur Heart J 1992; 11: 28–32. Hansteen V. Beta blockade after myocardial infarction: the Norwegian Propranolol Study in high-risk patients. Circulation 1983; 67 (suppl I): I-57–I-60. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–07. Kennedy HL, Brooks MM, Barker AH, et al. Beta-blocker therapy in the Cardiac Arrhythmia Suppression Trial. Am J Cardiol 1994; 74: 674–80. Aronow WS, Ahn C, Mercando AD, Epstein S, Kronzon I. Effect of propranolol versus no antiarrhythmic drug on sudden cardiac death, total cardiac death, and total death in patients 62 years of age with heart disease, complex ventricular arrhythmias, and left ventricular ejection fraction 40%. Am J Cardiol 1994; 74: 267–70. Aronow WS, Ahn C, Mercando AD, Epstein S., Kronzon I. Decrease of mortality by propranolol in patients with heart disease and complex ventricular arrhythmias is more an anti-ischemic than an antiarrhythmic effect. Am J Cardiol 1994; 74: 613–15. Aronow WS, Ahn C, Mercando AD, Epstein S. Circadian variation of sudden cardiac death or fatal myocardial infarction is abolished by propranolol in patients with heart disease and complex ventricular arrhythmias. Am J Cardiol 1994; 74: 819–21. Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden death. Eur Heart J 1992; 12 (suppl D): 111–20. Olsson G, Tuomilehto J, Berglund G, et al. Primary prevention of sudden cardiovascular death in hypertensive patients: mortality results from the MAPHY Study. Am J Hypertens 1991; 4: 151–58. MRC Working Party. Medical Research Council Trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Coope J, Warrender TS. Randomised trial of the treatment of hypertension in elderly patients in primary care. BMJ 1986; 293: 1145–51. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984; 77: 18–22. Aronow WS, Epstein SE, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic left ventricular hypertrophy, ventricular tachycardia and complex ventricular arrhythmias in predicting ventricular fibrillation or sudden cardiac death in elderly patients. Am J Cardiol 1988; 62: 1124–25. Aronow WS, Ahn C, Kronzon I, Gutstein H. Association of left ventricular hypertrophy and chronic atrial fibrillation with the incidence of new thromboembolic stroke in 2,384 older persons. Am J Cardiol 1999; 84: 468–69. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946–52. Aronow WS, Ahn C, Mercando AD, Epstein S. Correlation of atrial fibrillation, paroxysmal supraventricular tachycardia, and sinus rhythm with incidences of new coronary events in 1,359 patients, mean age 81 years, with heart disease. Am J Cardiol 1995; 75: 182–84.
THE LANCET • Vol 362 • August 23, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet