PMID- 11526365
OWN - NLM
STAT- MEDLINE
DCOM- 20010920
LR  - 20131121
IS  - 0002-8703 (Print)
IS  - 0002-8703 (Linking)
VI  - 142
IP  - 3
DP  - 2001 Sep
TI  - Challenges of subgroup analyses in multinational clinical trials: experiences 
      from the MERIT-HF trial.
PG  - 502-11
AB  - 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.
FAU - Wedel, H
AU  - Wedel H
AD  - Nordic School of Public Health, Sahlgrenska University Hospital, Goteborg, 
      Sweden.
FAU - Demets, D
AU  - Demets D
FAU - Deedwania, P
AU  - Deedwania P
FAU - Fagerberg, B
AU  - Fagerberg B
FAU - Goldstein, S
AU  - Goldstein S
FAU - Gottlieb, S
AU  - Gottlieb S
FAU - Hjalmarson, A
AU  - Hjalmarson A
FAU - Kjekshus, J
AU  - Kjekshus J
FAU - Waagstein, F
AU  - Waagstein F
FAU - Wikstrand, J
AU  - Wikstrand J
CN  - MERIT-HF Study Group
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am Heart J
JT  - American heart journal
JID - 0370465
RN  - 0 (Adrenergic beta-Antagonists)
RN  - GEB06NHM23 (Metoprolol)
SB  - IM
MH  - Adrenergic beta-Antagonists/administration & dosage/*therapeutic use
MH  - Adult
MH  - Aged
MH  - Female
MH  - Heart Failure/*drug therapy
MH  - Humans
MH  - International Cooperation
MH  - Male
MH  - Metoprolol/administration & dosage/*therapeutic use
MH  - Middle Aged
MH  - Proportional Hazards Models
MH  - *Randomized Controlled Trials as Topic
MH  - Reproducibility of Results
MH  - Research Design
MH  - Risk Factors
MH  - Sample Size
MH  - Survival Analysis
EDAT- 2001/08/30 10:00
MHDA- 2001/09/21 10:01
CRDT- 2001/08/30 10:00
PHST- 2001/08/30 10:00 [pubmed]
PHST- 2001/09/21 10:01 [medline]
PHST- 2001/08/30 10:00 [entrez]
AID - S0002-8703(01)33466-X [pii]
AID - 10.1067/mhj.2001.117600 [doi]
PST - ppublish
SO  - Am Heart J. 2001 Sep;142(3):502-11. doi: 10.1067/mhj.2001.117600.