Effect of on Cause-Specific Mortality in Heart Failure Patients The in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Program Scott D. Solomon, MD; Duolao Wang, PhD; Peter Finn, MD; Hicham Skali, MD; Leonardo Zornoff, MD; John J.V. McMurray, MD; Karl Swedberg, MD; Salim Yusuf, MD; Christopher B. Granger, MD; Eric L. Michelson, MD; Stuart Pocock, PhD; Marc A. Pfeffer, MD, PhD Downloaded from http://circ.ahajournals.org/ by guest on July 4, 2018 Background Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Methods and Results The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n 2028; LVEF 40% and ACE intolerant), CHARM-Added (n 2548; LVEF 40%, already on ACE inhibitors), and CHARM-Preserved (n 3023; LVEF 40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the patients, 8.5% died suddenly, and 6.2% died of progressive heart failure. reduced both sudden death (HR 0.85 [0.73 to 0.99], P 0.036) and death from worsening heart failure (HR 0.78 [0.65 to 0.94], P 0.008). These reductions were most apparent in the patients with LVEF 40%. Conclusions reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patients with systolic dysfunction. (Circulation. 2004;110: 2180-2183.) Key Words: heart failure candesartan receptor, angiotensin death, sudden In clinical trials of chronic heart failure (CHF), the majority of patients who die do so suddenly or from progressive pump failure. 1 In heart failure patients, angiotensinconverting enzyme (ACE) inhibitors and -blockers reduce overall mortality by reducing cardiovascular death, and specifically by reducing sudden death and death attributed to progressive heart failure. In the in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program, treatment with an angiotensin receptor blocker (ARB) led to a 12% risk reduction in cardiovascular death and a 9% borderline significant risk reduction in total mortality. We now describe the effect of candesartan on cause-specific mortality in CHARM. Methods CHARM consisted of 3 component trials in patients with CHF: CHARM-Alternative (n 2028; LVEF 40% and ACE intolerant), CHARM-Added (n 2548; LVEF 40%, already on ACE inhibitors), and CHARM-Preserved (n 3023; LVEF 40%). 2 4 Patients were randomized to candesartan, 4 or 8 mg titrated to 32 mg once daily, or matching placebo and were followed up for a median of 37.7 months. All 3 trials were pooled to provide adequate statistical power to evaluate cause-specific mortality. 5 Only the overall study not the component trials was powered to address the effect of candesartan on total mortality. Deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. Deaths were considered cardiovascular unless a specific noncardiovascular cause was identified and were further categorized as sudden or as attributed to myocardial infarction (MI), heart failure, stroke, complications of a procedure, or another cardiovascular cause. Sudden death was defined as the unexpected death of a stable patient. Heart failure death was defined as death in the setting of clinical progressive heart failure with no other apparent cause. MI death required autopsy, cardiac marker, or ECG evidence of infarction. Noncardiovascular deaths were subcategorized as cancer or other cause. Received May 5, 2004; revision received August 10, 2004; accepted August 18, 2004. From the Cardiovascular Division, Brigham and Women s Hospital, Boston, Mass (S.D.S., P.F., H.S., L.Z., M.A.P.); Sahlgrenska University Hospital/Östra, Göteborg, Sweden (K.S.); Duke University Medical Center, Durham, NC (C.B.G.); University of Glasgow, Glasgow, UK (J.J.V.M.); AstraZeneca LP, Wilmington, Del (E.L.M.); and Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada (S.Y.). Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02445. E-mail ssolomon@rics.bwh.harvard.edu 2004 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000144474.65922.AA 2180
Solomon et al and Cause of Death in CHARM 2181 Number, Proportion, and Annualized Incidence of Deaths Attributed to Different Causes in the 3 CHARM Trials and the Overall CHARM Program CHARM-Alternative CHARM-Added CHARM-Preserved CHARM-Overall Downloaded from http://circ.ahajournals.org/ by guest on July 4, 2018 Cause of Death (n 1013) (n 1015) (n 1276) (n 1272) (n 1514) (n 1508) (n 3803) (n 3796) Hazard Ratio and 95% CI Sudden death 80 (7.9) 111 (10.9) 150 (11.8) 168 (13.2) 69 (4.6) 65 (4.3) 299 (7.9) 344 (9.1) 0.85 (0.73 0.99) Incidence rate* 3.0 4.3 3.9 4.5 1.6 1.5 2.7 3.2 P 0.036 Progressive HF 70 (6.9) 89 (8.8) 91 (7.1) 117 (9.2) 48 (3.2) 54 (3.6) 209 (5.5) 260 (6.8) 0.78 (0.65 0.94) Incidence rate* 2.6 3.5 2.4 3.1 1.1 1.2 1.9 2.4 P 0.008 MI 34 (3.4) 17 (1.7) 18 (1.4) 21 (1.6) 9 (0.6) 12 (0.8) 61 (1.6) 50 (1.3) 1.19 (0.82 1.73) Incidence rate* 1.3 0.66 0.47 0.56 0.20 0.27 0.56 0.47 P 0.37 Stroke 13 (1.3) 15 (1.5) 15 (1.2) 13 (1.0) 17 (1.1) 16 (1.1) 45 (1.2) 44 (1.2) 1.00 (0.66 1.52) Incidence rate* 0.49 0.58 0.39 0.35 0.38 0.36 0.41 0.41 P 0.99 Procedure related 6 (0.6) 4 (0.4) 10 (0.8) 2 (0.2) 7 (0.5) 6 (0.4) 23 (0.6) 12 (0.3) 1.87 (0.93 3.77) Incidence rate* 0.23 0.15 0.26 0.05 0.16 0.14 0.21 0.11 P 0.073 Other CV 16 (1.6) 16 (1.6) 17 (1.3) 26 (2.0) 18 (1.2) 17 (1.1) 51 (1.3) 59 (1.6) 0.84 (0.58 1.23) Incidence rate* 0.60 0.62 0.44 0.70 0.41 0.39 0.47 0.55 P 0.37 All CV death 219 (21.6) 252 (24.8) 302 (23.7) 347 (27.3) 170 (11.2) 170 (11.3) 691 (18.2) 769 (20.3) 0.88 (0.79 0.97) Incidence rate* 8.2 9.8 7.9 9.3 3.8 3.9 6.3 7.2 P 0.012 Cancer death 25 (2.5) 18 (1.8) 35 (2.7) 19 (1.5) 26 (1.7) 22 (1.5) 86 (2.3) 59 (1.5) 1.42 (1.02 1.98) Incidence rate* 0.94 0.70 0.91 0.51 0.59 0.50 0.79 0.55 P 0.037 Other non-cv death 21 (2.1) 26 (2.6) 40 (3.1) 46 (3.6) 48 (3.2) 45 (3.0) 109 (2.9) 117 (3.1) 0.91 (0.70 1.18) Incidence rate* 0.79 1.01 1.04 1.24 1.08 1.03 1.00 1.09 P 0.81 All non-cv death 46 (4.5) 44 (4.3) 75 (5.9) 65 (5.1) 74 (4.9) 67 (4.4) 195 (5.1) 176 (4.6) 1.08 (0.88 1.33) Incidence rate* 1.7 1.7 2.0 1.8 1.7 1.5 1.8 1.7 P 0.45 All deaths 265 (26.2) 296 (29.2) 377 (29.6) 412 (32.4) 244 (16.1) 237 (15.7) 886 (23.3) 945 (24.9) 0.91 (0.83 1.00) Incidence rate* 10.0 11.5 9.8 11.1 5.5 5.4 8.1 8.8 P 0.055 *Per 100 person-years. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Hazard ratios were calculated for the treatment differences in the overall program utilizing a Cox proportional hazards model, 6 and the analysis was stratified by individual trial. A formal test for heterogeneity was performed to determine whether the effect of candesartan on individual cause of death was heterogenous among the 3 trials. We used SAS version 8.2 (SAS Institute, Cary, NC) for all statistical analyses. Results The demographic details of the CHARM population have been previously reported. 2 Briefly, the mean age was 66 years, 68.4% of patients were male, and 43% had ejection fraction 40%. All-cause and cause-specific mortality results are shown in the Table. Of 1831 deaths, 1460 were cardiovascular. Of all the patients, 8.5% had sudden death (35% of all deaths), and 6.2% died of progressive heart failure (26% of all deaths). Death attributed to MI (1.5% of patients, 6.1% of deaths), stroke (1.2% of patients, 4.9% of deaths), procedures (0.5% of patients, 1.9% of deaths), and other cardiovascular causes (1.4% of patients, 6.0% of deaths) were less common. Of the 371 noncardiovascular deaths (4.9% of patients and 20.3% of deaths), 145 were cancer related (1.9% of patients), and 226 (3.0% of patients) were attributed to other noncardiovascular causes. The reduction in cardiovascular death with candesartan 2 (HR 0.88 [0.79 to 0.97], P 0.012) was largely attributed to a reduction in both sudden death (HR 0.85 [0.73 to 0.99], P 0.036) and heart failure death (HR 0.78 [0.65 to 0.94], P 0.008). These reductions occurred only in the 2 low- LVEF trials. Noncardiovascular death was not affected by treatment. As previously reported, death attributed to cancer was more frequent in the candesartan group (HR 1.42 [1.02 to 1.98], P 0.037). The incidence rates of death and cardiovascular death were considerably lower in the Preserved trial than in the low-lvef trials. The rates of noncardiovascular death were similar across trials but accounted for a lower proportion of deaths in the patients with LVEF 40% (17%) compared with patients in the Preserved trial (29%). Discussion The majority of deaths in CHARM, which included a wide range of patients with CHF, were cardiovascular, and most were sudden or attributed to heart failure. The overall reduction in cardiovascular mortality associated with candesartan 2 was attributed to fewer sudden deaths and heart failure deaths, with no reduction in deaths attributed to MI or stroke, although these were relatively infrequent. The reductions in both sudden and heart failure death attributed to candesartan were predominantly observed in the patients with LVEF 40%. The low rate of death from MI and stroke is consistent with other trials in patients with low-lvef CHF. 7,8 CHARM also
2182 Circulation October 12, 2004 Downloaded from http://circ.ahajournals.org/ by guest on July 4, 2018 provides additional information on the causes of death in patients with CHF and preserved LVEF. Overall mortality was lower in these patients compared with patients with reduced LVEF, and the proportion of noncardiovascular deaths was higher. Neither the absolute number nor the proportion of deaths attributed to MI or stroke was higher in the Preserved trial, even though these patients were older and more hypertensive than in the reduced-lvef trials. 5 The proportion of cardiovascular deaths that were sudden or attributed to heart failure was similar across the 3 trials. The mechanisms by which an ARB may reduce the likelihood of progressive heart failure leading to death are well established and similar to the mechanisms postulated for the benefit observed with ACE inhibitors. These include a myriad of hemodynamic and neurohormonal actions, 9 reduction in ventricular dilatation and remodeling, 10 and reduction in sympathetic tone. 11 The mechanisms whereby ARBs reduce the incidence of sudden death in patients with CHF remain less clear (as they are also for ACE inhibitors). Overall improvement in hemodynamic status and attenuation of ventricular remodeling may directly and indirectly decrease the propensity to fatal ventricular arrhythmia. 12 ARBs, like ACE inhibitors, are potassium sparing, and relative increases in serum potassium may further reduce the arrhythmia risk. Reductions in the incidence of sudden death have been observed in trials with ACE inhibitors, 13 and in the Randomized ALdactone (spironolactone) Evaluation Study for congestive heart failure (RALES) and Eplerenone Post- AMI Heart failure Efficacy and SUrvival Study (EPHESUS) trials with the aldosterone antagonists. 8,14 That ARBs should display effects with regard to sudden death and death due to progressive heart failure that are similar to the effects of ACE inhibitors is even less surprising in light of recent data from the post-mi VALsartan In Acute myocardial infarction Trial (VALIANT) trial in which, in a direct comparison, the ARB valsartan was similar to captopril with regard to all primary end points. 15 Although the effect of candesartan on sudden death and death due to progressive heart failure appears to be most pronounced in the low-lvef populations, it is important to note that only the pooled CHARM overall study was designed and adequately powered to address the effect of candesartan on total mortality. The primary end point in the component trials, in contrast, was heart failure hospitalization or cardiovascular death. We have thus reported the hazard ratios and 95% confidence intervals for the individual causes of death only in the overall results. Because of the lack of power in the component trials, we resist drawing conclusions from the numeric differences in causes of death among the various component trials. Indeed, a formal statistical test of heterogeneity did not reveal any heterogeneity in any of the individual cause-of-death end points between trials, although we cannot exclude the possibility that with larger sample sizes we may have seen differences in the effect of candesartan in the different populations. Some limitations of this analysis should be noted. The ability to classify cause of death is always limited by the accuracy and availability of clinical information, standardization of the adjudication process, and consistency across the trial. The central adjudication methodology used in CHARM was designed to ensure consistency. Sudden death in a clinical trial does not imply causality, and there is inherent uncertainty in this classification. Although arrhythmia is presumed in many patients who die suddenly, other causes of sudden death include acute myocardial infarction, pulmonary embolism, aortic dissection, and stroke. In autopsied patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial, myocardial infarction was a frequent cause of death in autopsied patients who died suddenly. 16 Autopsy data were available in only a minority of patients in CHARM. It is, however, likely that some of the deaths classified as sudden death were fatal infarctions. Finally, although this study was not powered to address differences in the effect of candesartan on total mortality in the component trials, we also lack the statistical power to detect moderate increases or reductions in mortality from events such as MI, stroke, or procedure-related deaths, where the event rate was very low. In summary, the reduction in cardiovascular deaths produced by candesartan in a broad spectrum of CHF patients can be attributed to both reduced sudden death and death attributed to heart failure, but not death attributed to MI, stroke, procedures, or other cardiovascular causes. This benefit was observed primarily in patients with reduced ejection fraction. Disclosure Drs Solomon, Pfeffer, Swedberg, Granger, McMurray, and Yusuf have served as consultants to or received research grants and honoraria from AstraZeneca and other major cardiovascular pharmaceutical companies. Drs Pocock, Wang, Skali, Finn, and Zornoff have received research support form AstraZeneca. Dr Michelson is an employee of AstraZeneca. References 1. Garg R, Yusuf S. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995; 273:1450 1456. 2. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759 766. 3. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772 776. 4. 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Effect of on Cause-Specific Mortality in Heart Failure Patients: The in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Program Scott D. Solomon, Duolao Wang, Peter Finn, Hicham Skali, Leonardo Zornoff, John J.V. McMurray, Karl Swedberg, Salim Yusuf, Christopher B. Granger, Eric L. Michelson, Stuart Pocock and Marc A. Pfeffer Downloaded from http://circ.ahajournals.org/ by guest on July 4, 2018 Circulation. 2004;110:2180-2183; originally published online October 4, 2004; doi: 10.1161/01.CIR.0000144474.65922.AA Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2004 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/110/15/2180 An erratum has been published regarding this article. Please see the attached page for: /content/111/3/378.4.full.pdf Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2005/01/24/01.cir.0000144474.65922.aa.dc1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Corrections In the article by Huynh et al, Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery, which published in the June 26, 2001, issue (Circulation. 2001;103:3069 3074), the authors now realize errors appeared in Tables 3 and 4. The percentages of events and complications were presented on the basis of the number of patients visits rather than on the total number of patients. Overall, the corrected results did not change the implication of the study. There was no benefit of warfarin alone or combined with aspirin in the secondary prevention of ischemic events in this study of patients with previous coronary artery bypass surgery and an acute coronary syndrome; there was a significant excess in minor bleeding compared with the aspirin-alone group. Corrected versions of Tables 3 and 4 appear below. TABLE 3. End-Point Events According to Treatment Events Warfarin (n 45) Aspirin (n 46) Warfarin Aspirin (n 44) P Primary end point, n (%) 18 (40.0) 13 (28.3) 11 (25.0) 0.27 Death, n (%) 1 (2.2) 0 (0.0) 2 (4.5) 0.34 MI, n (%) 4 (8.9) 1 (2.2) 2 (4.5) 0.34 UA, n (%) 16 (35.6) 13 (28.3) 10 (22.7) 0.41 PCI, n (%) 6 (13.3) 1 (2.2) 3 (6.8) 0.12 Repeat CABG, n (%) 2 (4.4) 2 (4.3) 2 (4.5) 0.99 UA indicates unstable angina requiring rehospitalization; PCI, percutaneous coronary intervention; and MI, myocardial infarction. Primary end point is any-cause mortality, MI, or UA requiring hospitalization. TABLE 4. Complications and Adherence to Protocol by Patients Complications Warfarin (n 45) Aspirin (n 46) Warfarin Aspirin (n 44) P Minor bleeding, n (%) 10 (22.2) 2 (4.3) 9 (20.5) 0.03 Major bleeding, n (%) 1 (2.2) 0 (0.0) 2 (4.5) 0.34 Blood transfusions, n (%) 2 (4.4) 0 (0.0) 2 (4.5) 0.34 Compliance, %* 90.1 86.7 86.1 0.66 Protocol completion, %* 77.6 78.5 69.9 0.22 *Compliance and protocol completion were calculated per visit. DOI: 10.1161/01.CIR.0000155489.11621.70 (Circulation. 2005;111:377-379.) 2005 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org 377
378 Corrections In the article by Haïssaguerre et al, Mapping and Ablation of Ventricular Fibrillation Associated With Long-QT and Brugada Syndromes, which appeared in the August 26, 2003, issue (Circulation. 2003;108:925 928), the authors would like to note the following errors: 1. In the byline, Jerónimo Farré s name incorrectly appeared as Gerónimo Farre. 2. José Angel Cabrera and Jerónimo Farré work at Fundación Jiménez Díaz in Madrid, Spain. 3. The work of Drs Cabrera and Farré was supported by Redes Temáticas de Cooperación, Red Cardiovascular C01/03. DOI: 10.1161/01.CIR.0000155483.25082.D4 In the article by McRae and Ginsberg, Initial Treatment of Venous Thromboembolism, which appeared in the August 31, 2004, supplement sponsored by the Society for Vascular Medicine and Biology (Circulation. 2004;110[suppl I]:I-3 I-9), an error appeared in Table 2. The footnote of the table erroneously states that For enoxaparin, 100 anti-xa U/kg corresponds to a dose of 100 mg/kg. The legend should have read, For enoxaparin, 100 anti-xa U/kg corresponds to a dose of 1 mg/kg. DOI: 10.1161/01.CIR.0000155484.25082.1A In the article by Bauer et al, Acute Improvement in Global and Regional Left Ventricular Systolic Function After Percutaneous Heart Valve Implantation in Patients With Symptomatic Aortic Stenosis, which appeared in the September 14, 2004, issue (Circulation. 2004;110:1473 1476), two errors of note appeared in the table on page 1474. Under Endocardiographic data, the rows for LV end-systolic volume, mm Hg and LV end-diastolic volume, mm Hg should have appeared as the following: LV end-diastolic volume, ml LV end-systolic volume, ml 102 36 (baseline) 49 25 (baseline) DOI: 10.1161/01.CIR.0000155485.32706/1C Because of a typesetting error, several mathematical symbols appeared incorrectly in the article by Solomon et al, Effect of on Cause-Specific Mortality in Heart Failure Patients: The in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Program, which appeared in the October 12, 2004, issue (Circulation. 2004;110:2180 2183). On page 2180, in the abstract and in the text of the article, there were several instances in which LVEF 40% should have appeared as LVEF 40%. In addition, in the last sentence of the first paragraph of the article, please note that 9% borderline risk should read 9% borderline significant risk. The corrected version is available online at http://circ.ahajournals.org/cgi/ content/full/110/15/2180. (The previous version can be accessed by selecting the Previous Version of This Article link.) We regret these errors. DOI: 10.1161/01.CIR.0000155486.26868.C9 In the AHA Scientific Statement by Drew et al, Practice Standards for Electrocardiographic Monitoring in Hospital Settings: An American Heart Association Scientific Statement From the Councils on Cardiovascular Nursing, Clinical Cardiology, and Cardiovascular Disease in the Young, which appeared in the October 26, 2004, issue (Circulation. 2004;110:2721 2746), Figure 4 contained an error. The text in the figure refers to the Angle of Lewis. The correct name is Angle of Louis. The Association regrets this error. DOI: 10.1161/01.CIR.00001155490.19245.B0
Correction 379 In the article by Noujaim et al, From Mouse to Whale: A Universal Scaling Relation for the PR Interval of the Electrocardiogram of Mammals, which appeared in the November 2, 2004, issue (Circulation. 2004;110:2802 2808), the name of Ary L. Goldberger, MD, was misspelled as Goldberg in reference 12. The authors regret this error. DOI: 10.1161/01.CIR.0000155482.89456.78 In the article by Spargias et al, Ascorbic Acid Prevents Contrast-Mediated Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention, which appeared in the November 2, 2004, issue (Circulation. 2004;110:2837 2842), the name of author Panagiotis Iokovis was spelled incorrectly as Panagiotis Iocovis. The authors regret this error. DOI: 10.1161/01.CIR.0000155487.34492.0D In the article by Francia et al, Deletion of p66 shc Gene Protects Against Age-Related Endothelial Dysfunction, which published in the November 2, 2004, issue (Circulation. 2004;110:2889 2895), the name of author Chiara Delli Gatti incorrectly appeared with a lower case d (ie, delli Gatti ). DOI: 10.1161/01.CIR.0000155488.34492.E9
Effect of on Cause-Specific Mortality in Heart Failure Patients The in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Program Scott D. Solomon, MD; Duolao Wang, PhD; Peter Finn, MD; Hicham Skali, MD; Leonardo Zornoff, MD; John J.V. McMurray, MD; Karl Swedberg, MD; Salim Yusuf, MD; Christopher B. Granger, MD; Eric L. Michelson, MD; Stuart Pocock, PhD; Marc A. Pfeffer, MD, PhD Background Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Methods and Results The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n 2028; LVEF 40% and ACE intolerant), CHARM-Added (n 2548; LVEF 40%, already on ACE inhibitors), and CHARM-Preserved (n 3023; LVEF 40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the patients, 8.5% died suddenly, and 6.2% died of progressive heart failure. reduced both sudden death (HR 0.85 [0.73 to 0.99], P 0.036) and death from worsening heart failure (HR 0.78 [0.65 to 0.94], P 0.008). These reductions were most apparent in the patients with LVEF 40%. Conclusions reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patients with systolic dysfunction. (Circulation. 2004;110: 2180-2183.) Key Words: heart failure candesartan receptor, angiotensin death, sudden In clinical trials of chronic heart failure (CHF), the majority of patients who die do so suddenly or from progressive pump failure. 1 In heart failure patients, angiotensinconverting enzyme (ACE) inhibitors and -blockers reduce overall mortality by reducing cardiovascular death, and specifically by reducing sudden death and death attributed to progressive heart failure. In the in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program, treatment with an angiotensin receptor blocker (ARB) led to a 12% risk reduction in cardiovascular death and a 9% borderline risk reduction in total mortality. We now describe the effect of candesartan on cause-specific mortality in CHARM. Methods CHARM consisted of 3 component trials in patients with CHF: CHARM-Alternative (n 2028; LVEF 40% and ACE intolerant), CHARM-Added (n 2548; LVEF 40%, already on ACE inhibitors), and CHARM-Preserved (n 3023; LVEF 40%). 2 4 Patients were randomized to candesartan, 4 or 8 mg titrated to 32 mg once daily, or matching placebo and were followed up for a median of 37.7 months. All 3 trials were pooled to provide adequate statistical power to evaluate cause-specific mortality. 5 Only the overall study not the component trials was powered to address the effect of candesartan on total mortality. Deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. Deaths were considered cardiovascular unless a specific noncardiovascular cause was identified and were further categorized as sudden or as attributed to myocardial infarction (MI), heart failure, stroke, complications of a procedure, or another cardiovascular cause. Sudden death was defined as the unexpected death of a stable patient. Heart failure death was defined as death in the setting of clinical progressive heart failure with no other apparent cause. MI death required autopsy, cardiac marker, or ECG evidence of infarction. Noncardiovascular deaths were subcategorized as cancer or other cause. Received May 5, 2004; revision received August 10, 2004; accepted August 18, 2004. From the Cardiovascular Division, Brigham and Women s Hospital, Boston, Mass (S.D.S., P.F., H.S., L.Z., M.A.P.); Sahlgrenska University Hospital/Östra, Göteborg, Sweden (K.S.); Duke University Medical Center, Durham, NC (C.B.G.); University of Glasgow, Glasgow, UK (J.J.V.M.); AstraZeneca LP, Wilmington, Del (E.L.M.); and Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada (S.Y.). Correspondence to Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02445. E-mail ssolomon@rics.bwh.harvard.edu 2004 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000144474.65922.AA 2180
Solomon et al and Cause of Death in CHARM 2181 Number, Proportion, and Annualized Incidence of Deaths Attributed to Different Causes in the 3 CHARM Trials and the Overall CHARM Program CHARM-Alternative CHARM-Added CHARM-Preserved CHARM-Overall Cause of Death (n 1013) (n 1015) (n 1276) (n 1272) (n 1514) (n 1508) (n 3803) (n 3796) Hazard Ratio and 95% CI Sudden death 80 (7.9) 111 (10.9) 150 (11.8) 168 (13.2) 69 (4.6) 65 (4.3) 299 (7.9) 344 (9.1) 0.85 (0.73 0.99) Incidence rate* 3.0 4.3 3.9 4.5 1.6 1.5 2.7 3.2 P 0.036 Progressive HF 70 (6.9) 89 (8.8) 91 (7.1) 117 (9.2) 48 (3.2) 54 (3.6) 209 (5.5) 260 (6.8) 0.78 (0.65 0.94) Incidence rate* 2.6 3.5 2.4 3.1 1.1 1.2 1.9 2.4 P 0.008 MI 34 (3.4) 17 (1.7) 18 (1.4) 21 (1.6) 9 (0.6) 12 (0.8) 61 (1.6) 50 (1.3) 1.19 (0.82 1.73) Incidence rate* 1.3 0.66 0.47 0.56 0.20 0.27 0.56 0.47 P 0.37 Stroke 13 (1.3) 15 (1.5) 15 (1.2) 13 (1.0) 17 (1.1) 16 (1.1) 45 (1.2) 44 (1.2) 1.00 (0.66 1.52) Incidence rate* 0.49 0.58 0.39 0.35 0.38 0.36 0.41 0.41 P 0.99 Procedure related 6 (0.6) 4 (0.4) 10 (0.8) 2 (0.2) 7 (0.5) 6 (0.4) 23 (0.6) 12 (0.3) 1.87 (0.93 3.77) Incidence rate* 0.23 0.15 0.26 0.05 0.16 0.14 0.21 0.11 P 0.073 Other CV 16 (1.6) 16 (1.6) 17 (1.3) 26 (2.0) 18 (1.2) 17 (1.1) 51 (1.3) 59 (1.6) 0.84 (0.58 1.23) Incidence rate* 0.60 0.62 0.44 0.70 0.41 0.39 0.47 0.55 P 0.37 All CV death 219 (21.6) 252 (24.8) 302 (23.7) 347 (27.3) 170 (11.2) 170 (11.3) 691 (18.2) 769 (20.3) 0.88 (0.79 0.97) Incidence rate* 8.2 9.8 7.9 9.3 3.8 3.9 6.3 7.2 P 0.012 Cancer death 25 (2.5) 18 (1.8) 35 (2.7) 19 (1.5) 26 (1.7) 22 (1.5) 86 (2.3) 59 (1.5) 1.42 (1.02 1.98) Incidence rate* 0.94 0.70 0.91 0.51 0.59 0.50 0.79 0.55 P 0.037 Other non-cv death 21 (2.1) 26 (2.6) 40 (3.1) 46 (3.6) 48 (3.2) 45 (3.0) 109 (2.9) 117 (3.1) 0.91 (0.70 1.18) Incidence rate* 0.79 1.01 1.04 1.24 1.08 1.03 1.00 1.09 P 0.81 All non-cv death 46 (4.5) 44 (4.3) 75 (5.9) 65 (5.1) 74 (4.9) 67 (4.4) 195 (5.1) 176 (4.6) 1.08 (0.88 1.33) Incidence rate* 1.7 1.7 2.0 1.8 1.7 1.5 1.8 1.7 P 0.45 All deaths 265 (26.2) 296 (29.2) 377 (29.6) 412 (32.4) 244 (16.1) 237 (15.7) 886 (23.3) 945 (24.9) 0.91 (0.83 1.00) Incidence rate* 10.0 11.5 9.8 11.1 5.5 5.4 8.1 8.8 P 0.055 *Per 100 person-years. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Hazard ratios were calculated for the treatment differences in the overall program utilizing a Cox proportional hazards model, 6 and the analysis was stratified by individual trial. A formal test for heterogeneity was performed to determine whether the effect of candesartan on individual cause of death was heterogenous among the 3 trials. We used SAS version 8.2 (SAS Institute, Cary, NC) for all statistical analyses. Results The demographic details of the CHARM population have been previously reported. 2 Briefly, the mean age was 66 years, 68.4% of patients were male, and 43% had ejection fraction 40%. All-cause and cause-specific mortality results are shown in the Table. Of 1831 deaths, 1460 were cardiovascular. Of all the patients, 8.5% had sudden death (35% of all deaths), and 6.2% died of progressive heart failure (26% of all deaths). Death attributed to MI (1.5% of patients, 6.1% of deaths), stroke (1.2% of patients, 4.9% of deaths), procedures (0.5% of patients, 1.9% of deaths), and other cardiovascular causes (1.4% of patients, 6.0% of deaths) were less common. Of the 371 noncardiovascular deaths (4.9% of patients and 20.3% of deaths), 145 were cancer related (1.9% of patients), and 226 (3.0% of patients) were attributed to other noncardiovascular causes. The reduction in cardiovascular death with candesartan 2 (HR 0.88 [0.79 to 0.97], P 0.012) was largely attributed to a reduction in both sudden death (HR 0.85 [0.73 to 0.99], P 0.036) and heart failure death (HR 0.78 [0.65 to 0.94], P 0.008). These reductions occurred only in the 2 low- LVEF trials. Noncardiovascular death was not affected by treatment. As previously reported, death attributed to cancer was more frequent in the candesartan group (HR 1.42 [1.02 to 1.98], P 0.037). The incidence rates of death and cardiovascular death were considerably lower in the Preserved trial than in the low-lvef trials. The rates of noncardiovascular death were similar across trials but accounted for a lower proportion of deaths in the patients with LVEF 40% (17%) compared with patients in the Preserved trial (29%). Discussion The majority of deaths in CHARM, which included a wide range of patients with CHF, were cardiovascular, and most were sudden or attributed to heart failure. The overall reduction in cardiovascular mortality associated with candesartan 2 was attributed to fewer sudden deaths and heart failure deaths, with no reduction in deaths attributed to MI or stroke, although these were relatively infrequent. The reductions in both sudden and heart failure death attributed to candesartan were predominantly observed in the patients with LVEF 40%. The low rate of death from MI and stroke is consistent with other trials in patients with low-lvef CHF. 7,8 CHARM also
2182 Circulation October 12, 2004 provides additional information on the causes of death in patients with CHF and preserved LVEF. Overall mortality was lower in these patients compared with patients with reduced LVEF, and the proportion of noncardiovascular deaths was higher. Neither the absolute number nor the proportion of deaths attributed to MI or stroke was higher in the Preserved trial, even though these patients were older and more hypertensive than in the reduced-lvef trials. 5 The proportion of cardiovascular deaths that were sudden or attributed to heart failure was similar across the 3 trials. The mechanisms by which an ARB may reduce the likelihood of progressive heart failure leading to death are well established and similar to the mechanisms postulated for the benefit observed with ACE inhibitors. These include a myriad of hemodynamic and neurohormonal actions, 9 reduction in ventricular dilatation and remodeling, 10 and reduction in sympathetic tone. 11 The mechanisms whereby ARBs reduce the incidence of sudden death in patients with CHF remain less clear (as they are also for ACE inhibitors). Overall improvement in hemodynamic status and attenuation of ventricular remodeling may directly and indirectly decrease the propensity to fatal ventricular arrhythmia. 12 ARBs, like ACE inhibitors, are potassium sparing, and relative increases in serum potassium may further reduce the arrhythmia risk. Reductions in the incidence of sudden death have been observed in trials with ACE inhibitors, 13 and in the Randomized ALdactone (spironolactone) Evaluation Study for congestive heart failure (RALES) and Eplerenone Post- AMI Heart failure Efficacy and SUrvival Study (EPHESUS) trials with the aldosterone antagonists. 8,14 That ARBs should display effects with regard to sudden death and death due to progressive heart failure that are similar to the effects of ACE inhibitors is even less surprising in light of recent data from the post-mi VALsartan In Acute myocardial infarction Trial (VALIANT) trial in which, in a direct comparison, the ARB valsartan was similar to captopril with regard to all primary end points. 15 Although the effect of candesartan on sudden death and death due to progressive heart failure appears to be most pronounced in the low-lvef populations, it is important to note that only the pooled CHARM overall study was designed and adequately powered to address the effect of candesartan on total mortality. The primary end point in the component trials, in contrast, was heart failure hospitalization or cardiovascular death. We have thus reported the hazard ratios and 95% confidence intervals for the individual causes of death only in the overall results. Because of the lack of power in the component trials, we resist drawing conclusions from the numeric differences in causes of death among the various component trials. Indeed, a formal statistical test of heterogeneity did not reveal any heterogeneity in any of the individual cause-of-death end points between trials, although we cannot exclude the possibility that with larger sample sizes we may have seen differences in the effect of candesartan in the different populations. Some limitations of this analysis should be noted. The ability to classify cause of death is always limited by the accuracy and availability of clinical information, standardization of the adjudication process, and consistency across the trial. The central adjudication methodology used in CHARM was designed to ensure consistency. Sudden death in a clinical trial does not imply causality, and there is inherent uncertainty in this classification. Although arrhythmia is presumed in many patients who die suddenly, other causes of sudden death include acute myocardial infarction, pulmonary embolism, aortic dissection, and stroke. In autopsied patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial, myocardial infarction was a frequent cause of death in autopsied patients who died suddenly. 16 Autopsy data were available in only a minority of patients in CHARM. It is, however, likely that some of the deaths classified as sudden death were fatal infarctions. Finally, although this study was not powered to address differences in the effect of candesartan on total mortality in the component trials, we also lack the statistical power to detect moderate increases or reductions in mortality from events such as MI, stroke, or procedure-related deaths, where the event rate was very low. In summary, the reduction in cardiovascular deaths produced by candesartan in a broad spectrum of CHF patients can be attributed to both reduced sudden death and death attributed to heart failure, but not death attributed to MI, stroke, procedures, or other cardiovascular causes. This benefit was observed primarily in patients with reduced ejection fraction. Disclosure Drs Solomon, Pfeffer, Swedberg, Granger, McMurray, and Yusuf have served as consultants to or received research grants and honoraria from AstraZeneca and other major cardiovascular pharmaceutical companies. Drs Pocock, Wang, Skali, Finn, and Zornoff have received research support form AstraZeneca. Dr Michelson is an employee of AstraZeneca. References 1. Garg R, Yusuf S. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995; 273:1450 1456. 2. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759 766. 3. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772 776. 4. 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