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Correspondence |

Cause of Death in the SMART Trial FREE TO VIEW

Craig Williams, PharmD
Author and Funding Information

Affiliations: Wishard Hospital, Indianapolis, IN,  National Jewish Research and Medical Center, Denver, CO,  GlaxoSmithKline, Research Triangle Park, NC

Correspondence to: Craig Williams, Purdue University, Pharmacy Practice, W7555 Myers Building, Wishard Hospital, 1001 West 10th St, Indianapolis, IN 46202; e-mail: cdwilli@iupui.edu



Chest. 2006;130(3):929-930. doi:10.1378/chest.130.3.929-a
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To the Editor:

The Salmeterol Multicenter Asthma Research Trial (SMART)1 found a higher incidence of death in African Americans with salmeterol therapy compared to placebo. The authors speculated on possible genetic causes, mentioning β-receptor polymorphisms. But another genetic aspect is worth considering.

Inhaled β-agonists significantly prolong the QTc interval in a dose-dependent and gene-dependent manner.23 While the prolongation of QTc is a risk for torsades de pointes, a necessary cofactor appears to be increased transmural dispersion of repolarization.3 Transmural dispersion of repolarization is sympathetically mediated and has been demonstrated to increase with therapy with systemic β-agonists, but is likely affected by inhaled agents as well.23

The race aspects of the findings in the SMART are particularly interesting because the risk of drug-induced torsades de pointes with β-agonist therapy is dependent on genetic polymorphisms for the genes associated with the long QT syndrome.3It has been shown that African Americans have substantially greater heterogeneity in those genes, a finding of as yet still unknown consequence.4 While we are in the process of conducting a trial comparing the effects of albuterol on QTc in asthmatic patients compared to nonasthmatic patients, it would be helpful to know specifically what the cause of death was in the SMART trial in the 11 patients who died while receiving salmeterol, but whose causes of death were not ruled to be asthma and thus were not detailed in the study.

Additionally, of the 13 reported deaths in the salmeterol group that were ruled to be asthma-related, 7 listed either no cause of death or a primary cardiovascular disorder on the death certificate (Table 5 in the article by Nelson et al1). While I noted that a coroners report was available for one patient, it would be helpful to know whether further autopsy data are available or are being sought since previous series5 have reported autopsy findings that are inconsistent with a pulmonary cause of death in patients who have been reported to have died of asthma.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Dr. Nelson is a consultant, speaker, and recipient of research grants from GlaxoSmithKline, and was also a member of the Morbidity and Mortality Review Committee. Dr. Dorinsky is an employee of GlaxoSmithKline.

Nelson, HS, Weiss, ST, Bleecker, ER, et al (2006) The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.Chest129,15-26
 
Wong, CS, Pavord, ID, Williams, J, et al Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma.Lancet1990;336,1396-1399
 
Antzelevitch, C Sympathetic modulation of the long QT syndrome.Eur Heart J2002;23,1246-1252
 
Ackerman, MJ, Tester, DJ, Jones, GS, et al Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.Mayo Clin Proc2003;78,1479-1487
 
Copeland, AR Asthmatic deaths in the medical examiner’s population.Forensic Sci Int1986;31,7-12
 
To The Editor:

We find Dr. William’s letter quite interesting, particularly as it relates to polymorphisms within genes associated with the long-QT syndrome and the heterogeneity of these genes in African Americans.1 The protocol for Salmeterol Multicenter Asthma Research Trial (SMART) did not specify the collection of biological material for genotyping, which we acknowledge could have helped to clarify some of the observations seen in the African-American population. We do not have any more detailed information for the subjects in the salmeterol group who either had no listed cause of death or a primary cardiovascular cause, as the published information is all that is available.

Although β-agonists can produce ECG changes, prolongation of the QTc interval, and ST-segment depression, previous studies23 addressing the cardiovascular effects of salmeterol when taken at the recommended doses have not demonstrated an increase in QTc intervals or an increased incidence of supraventricular or ventricular ectopy. On the other hand, there is the possibility that some subjects in SMART could have taken doses of salmeterol that were higher than the recommended dose. Salmeterol, like all β2-agonists, may produce dose-related increases in cardiac electrophysiologic abnormalities. Even so, the numbers of serious adverse events in the cardiovascular system were similar for subjects in both treatment arms in SMART and occurred at a rate of < 1%.

References
Ackerman, MJ, Tester, DJ, Jones, GS, et al Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.Mayo Clin Proc2003;78,1479-1487
 
Chervinsky, P, Goldberg, P, Galant, S, et al Long-term cardiovascular safety of salmeterol powder pharmacotherapy in adolescent and adult patients with chronic persistent asthma.Chest1999;115,642-648
 
Shrewsbury, S, Hallett, C Salmeterol 100 μg: an analysis of its tolerability in single- and chronic-dose studies.Ann Allergy Asthma Immunol2001;87,465-473
 

Figures

Tables

References

Nelson, HS, Weiss, ST, Bleecker, ER, et al (2006) The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.Chest129,15-26
 
Wong, CS, Pavord, ID, Williams, J, et al Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma.Lancet1990;336,1396-1399
 
Antzelevitch, C Sympathetic modulation of the long QT syndrome.Eur Heart J2002;23,1246-1252
 
Ackerman, MJ, Tester, DJ, Jones, GS, et al Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.Mayo Clin Proc2003;78,1479-1487
 
Copeland, AR Asthmatic deaths in the medical examiner’s population.Forensic Sci Int1986;31,7-12
 
Ackerman, MJ, Tester, DJ, Jones, GS, et al Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.Mayo Clin Proc2003;78,1479-1487
 
Chervinsky, P, Goldberg, P, Galant, S, et al Long-term cardiovascular safety of salmeterol powder pharmacotherapy in adolescent and adult patients with chronic persistent asthma.Chest1999;115,642-648
 
Shrewsbury, S, Hallett, C Salmeterol 100 μg: an analysis of its tolerability in single- and chronic-dose studies.Ann Allergy Asthma Immunol2001;87,465-473
 
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