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Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial.

https://arctichealth.org/en/permalink/ahliterature10156
Source
Am Heart J. 2001 Sep;142(3):502-11
Publication Type
Article
Date
Sep-2001
Author
H. Wedel
D. Demets
P. Deedwania
B. Fagerberg
S. Goldstein
S. Gottlieb
A. Hjalmarson
J. Kjekshus
F. Waagstein
J. Wikstrand
Author Affiliation
Nordic School of Public Health, Sahlgrenska University Hospital, Göteborg, Sweden.
Source
Am Heart J. 2001 Sep;142(3):502-11
Date
Sep-2001
Language
English
Publication Type
Article
Keywords
Adrenergic beta-Antagonists - administration & dosage - therapeutic use
Adult
Aged
Female
Heart Failure, Congestive - drug therapy
Humans
International Cooperation
Male
Metoprolol - administration & dosage - therapeutic use
Middle Aged
Proportional Hazards Models
Randomized Controlled Trials
Reproducibility of Results
Research Design
Research Support, Non-U.S. Gov't
Risk factors
Sample Size
Survival Analysis
Abstract
BACKGROUND: International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of b-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. METHODS: The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. RESULTS: Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of.22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. CONCLUSIONS: Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial.
PubMed ID
11526365 View in PubMed
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Female sex is associated with increased mortality and morbidity early, but not late, after coronary artery bypass grafting.

https://arctichealth.org/en/permalink/ahliterature48266
Source
Eur Heart J. 1996 Sep;17(9):1426-31
Publication Type
Article
Date
Sep-1996
Author
G. Brandrup-Wognsen
H. Berggren
M. Hartford
A. Hjalmarson
T. Karlsson
J. Herlitz
Author Affiliation
Division of Thoracic and Cardiovascular Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
Source
Eur Heart J. 1996 Sep;17(9):1426-31
Date
Sep-1996
Language
English
Publication Type
Article
Keywords
Aged
Coronary Artery Bypass - mortality
Data Collection
Female
Follow-Up Studies
Humans
Male
Middle Aged
Morbidity
Multivariate Analysis
Postoperative Complications - epidemiology - physiopathology
Proportional Hazards Models
Prospective Studies
Research Support, Non-U.S. Gov't
Risk factors
Sex Factors
Survival Rate
Sweden
Time Factors
Abstract
OBJECTIVE: To describe mortality and morbidity during a period of 2 years after coronary artery bypass grafting in relation to gender. DESIGN: Prospective follow-up study. SETTING: Two regional cardiothoracic centres which performed all the coronary artery bypass operations in western Sweden at the time. SUBJECTS: A total of 2129 (1727 (81%) men and 402 (19%) women) consecutive patients undergoing coronary artery bypass surgery between June 1988 and June 1991 without concomitant procedures. RESULTS: Females were older and more frequently had a history of hypertension, diabetes mellitus, congestive heart failure, renal dysfunction and obesity. In a multivariate analysis, taking account of age, history of cardiovascular diseases and renal dysfunction, female sex appeared as a significant independent predictor of mortality during the 30 days after coronary artery bypass grafting (P
Notes
Comment In: Eur Heart J. 1997 Apr;18(4):6999129906
PubMed ID
8880029 View in PubMed
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Improvement of ED prediction of cardiac mortality among patients with symptoms suggestive of acute myocardial infarction.

https://arctichealth.org/en/permalink/ahliterature48225
Source
Am J Emerg Med. 1997 Jan;15(1):1-7
Publication Type
Article
Date
Jan-1997
Author
B W Karlson
J. Herlitz
U. Strömbom
J. Lindqvist
A. Oden
A. Hjalmarson
Author Affiliation
Division of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
Source
Am J Emerg Med. 1997 Jan;15(1):1-7
Date
Jan-1997
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aged, 80 and over
Chest Pain - mortality
Emergency Service, Hospital
Female
Humans
Male
Middle Aged
Myocardial Infarction - diagnosis - mortality
Prognosis
Proportional Hazards Models
Research Support, Non-U.S. Gov't
Risk factors
Survival Analysis
Sweden
Abstract
A study was undertaken to evaluate the 1-year risk of cardiac death for patients with chest pain/suspected acute myocardial infarction in the emergency department (ED) and express the prognosis in a statistical model. Clinical variables and electrocardiogram were correlated to cardiac death during 1 year. Cox regression model was used to estimate the risk of death as a continuous function of a risk score and the time interval. From these, the prognosis for each patient can be calculated. There were 6,794 visits by 5,303 patients followed for 1 year, during which 604 patients died. The absolute risk of cardiac death can be calculated from the independent predictors for cardiac death: age; sex; histories of diabetes mellitus, hypertension, and congestive heart failure; and symptoms, electrocardiographic pattern, and degree of suspicion of acute myocardial infarction on admission. This model allows estimation of the prognosis for every patient with chest pain/suspected acute myocardial infarction from data easily available in the ED.
PubMed ID
9002560 View in PubMed
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