On 2014 Nov 11, Eva Kottenberg commented:

Contrary to his statement, we have not been contacted by Dr. Berthelsen from Denmark. Also, contrary to his statement, ethics approval was explicitly mentioned in our paper (page 454 line 52). We had also clearly and explicitly reported in our paper, that our study is a retrospective analysis of a subgroup in an ongoing trial. Finally, we had specifically reported in which respect the patient selection of the current analysis differed from that of our prior Lancet paper. Dr. Berthelsen could have avoided his mathematical speculations simply by reading our paper much more carefully, so as to avoid obvious false statements which question the integrity and honesty of our scientific work. PD Dr. med. E. Kottenberg, Prof. Dr. med. J. Peters

On 2014 Oct 29, Eva Kottenberg commented:

None

On 2014 Oct 22, Preben Berthelsen commented:

Before accepting the authors’ results it must be realized that the conclusions are based on a non-randomized, unplanned, post hoc subgroup analysis of a larger study on remote ischaemic preconditioning in CABG surgery (ClinicalTrials NCT01406678). The results of the primary study were published in The Lancet (August 17, 2013). There are severe methodological problems with The Lancet paper as can be seen in the PubMed Commons comment to the paper (PMID:23953384).

In the present paper, the authors have selected, as a control group, 130 patients of the 167 controls included in the original Lancet paper. The patients were anaesthetized with isoflurane and no remote ischaemic preconditioning was used. The results are peculiar. The average 72h troponin release AUC in the original 167 patients was 321 (SD 213) and in the present subgroup of 130 patients 514 (SD 600). It is a mathematical impossibility that that so large a difference - in both mean and SD values - can be correct when 78% of the patients/results are shared. Furthermore, in the present study 14 of 130 (11%) are reported to be ACE/ARB treated while 75 of 167 (45%) in The Lancet paper are so treated. Again, it is not mathematically possible that the reported numbers are correct. I have tried to contact the corresponding author twice to determine if these discrepancies are printing errors. I have not received a response.

The authors have not statistically compared the difference in troponin release between sulphonylurea-treated diabetics and patients without diabetes. Their conclusions are instead solely based on within-group statistical analyses. And as Bland & Altman lucidly put it “this approach is biased and invalid, producing conclusions which are potentially highly misleading” (Trials 2011,12:264).

The investigation has no approval from an ethics committee. Taken in all, I feel it justified to view the results of this paper with scepticism. P.G.Berthelsen, Charlottenlund, Denmark.

On 2014 Oct 22, Preben Berthelsen commented:

Before accepting the authors’ results it must be realized that the conclusions are based on a non-randomized, unplanned, post hoc subgroup analysis of a larger study on remote ischaemic preconditioning in CABG surgery (ClinicalTrials NCT01406678). The results of the primary study were published in The Lancet (August 17, 2013). There are severe methodological problems with The Lancet paper as can be seen in the PubMed Commons comment to the paper (PMID:23953384).

In the present paper, the authors have selected, as a control group, 130 patients of the 167 controls included in the original Lancet paper. The patients were anaesthetized with isoflurane and no remote ischaemic preconditioning was used. The results are peculiar. The average 72h troponin release AUC in the original 167 patients was 321 (SD 213) and in the present subgroup of 130 patients 514 (SD 600). It is a mathematical impossibility that that so large a difference - in both mean and SD values - can be correct when 78% of the patients/results are shared. Furthermore, in the present study 14 of 130 (11%) are reported to be ACE/ARB treated while 75 of 167 (45%) in The Lancet paper are so treated. Again, it is not mathematically possible that the reported numbers are correct. I have tried to contact the corresponding author twice to determine if these discrepancies are printing errors. I have not received a response.

The authors have not statistically compared the difference in troponin release between sulphonylurea-treated diabetics and patients without diabetes. Their conclusions are instead solely based on within-group statistical analyses. And as Bland & Altman lucidly put it “this approach is biased and invalid, producing conclusions which are potentially highly misleading” (Trials 2011,12:264).

The investigation has no approval from an ethics committee. Taken in all, I feel it justified to view the results of this paper with scepticism. P.G.Berthelsen, Charlottenlund, Denmark.

On 2014 Oct 29, Eva Kottenberg commented:

None

On 2014 Nov 11, Eva Kottenberg commented:

Contrary to his statement, we have not been contacted by Dr. Berthelsen from Denmark. Also, contrary to his statement, ethics approval was explicitly mentioned in our paper (page 454 line 52). We had also clearly and explicitly reported in our paper, that our study is a retrospective analysis of a subgroup in an ongoing trial. Finally, we had specifically reported in which respect the patient selection of the current analysis differed from that of our prior Lancet paper. Dr. Berthelsen could have avoided his mathematical speculations simply by reading our paper much more carefully, so as to avoid obvious false statements which question the integrity and honesty of our scientific work. PD Dr. med. E. Kottenberg, Prof. Dr. med. J. Peters