Title:Determinants of high sensitivity cardiac troponin T elevation in acute ischemic stroke

Transcription

1 Author's response to reviews Title:Determinants of high sensitivity cardiac troponin T elevation in acute ischemic stroke Authors: Kashif W Faiz (kashif.faiz@medisin.uio.no) Bente Thommessen (bente.thommessen@ahus.no) Gunnar Einvik (gunnar.einvik@medisin.uio.no) Pål H Brekke (paul.brekke@gmail.com) Torbjørn Omland (torbjorn.omland@medisin.uio.no) Ole M Rønning (o.m.ronning@medisin.uio.no) Version:3Date:27 April 2014 Author's response to reviews: see over

2 Lørenskog, April 27 th 2014 BMC Neurology Dr. Fabienne Perren Cover letter regarding the second revision version of the manuscript no. MS: Determinants of high sensitivity cardiac troponin T elevation in acute ischemic stroke Dear Dr Perren, We are grateful for the thorough and insightful reviews of our paper, and appreciate the opportunity for resubmission. Please find below our point-to-point response to the reviewers comments (in italics). Our reply is given in bold, and the revised sections of our manuscript are given below in red colour. In our opinion the suggested changes from the reviewers have improved the manuscript and we hope you will find it acceptable for publication in BMC Neurology. On behalf of the authors, Yours sincerely Kashif Waqar Faiz, MD

3 Reviewer 1 1. The sentence in the abstract results starting with: Among patients with two values, is not clear; I would suggest to rephrase this sentence. Reply: We have rephrased the sentence in the abstract: Of the 182 patients who had two hs-ctnt measurements, 12 (6.6%) had both a rise or fall of hs-ctnt with at least one elevated value, and ECG manifestations of myocardial ischemia, e.g. meeting the criteria of acute MI. Among patients with two hs-ctnt values, 12 (6.6%) of 182 patients had both ECG manifestations of myocardial ischemia and rise or fall of hs-ctnt with at least one elevated value, e.g. meeting the criteria of acute MI. 2. In the Abstract conclusion, expressions such MI type 1 or type 2 should be avoided (it is to specific); More general discussion should be addressed. Reply: We agree that type 1 and type 2 MI is too specific, especially in an abstract, and have removed the last part of the sentence. Acute MI is likely underdiagnosed in acute ischemic stroke patients., but it is uncertain whether myocardial ischemia is caused by type 1 or type 2 MI. 3. An abbreviation list on the end of the manuscript would be helpful. Reply: We include an abbreviation list as a supplemental file in the revised version, and the Editor-in-Chief could include it if necessary. 3. The second reviewer addressed also the issue of multiple testing indicating that too many factors were tested. Was a statistician involved? Reply: We agree that too many variables were included in the multivariate analysis regarding dynamic change and in-hospital mortality, given the low event rate. In this revision, we have reduced the number of variables in the analysis (excluded congestive heart failure (correlation to coronary heart disease), tr-pa, hyperlipidemia and blood leukocyte count). Because we were interested in in-hospital mortality independent of hospital stay, we have used logistic regression analyses (and not Cox-regression). A statistician was not involved in this revision-phase. Table 4: p value Unadjusted OR (95% CI) P value Adjusted OR (95% CI) (1) hs-ctnt > 14 ng/l ( ) ( ) 1.15 ( ) log hs-ctnt ( ) ( ) 1.21 ( ) δ hs-ctnt 20% ( ) ( ) δ hs-ctnt 20% ( ) ( ) 5.35 ( ) δ hs-ctnt ( ) ( ) ng/l δ hs-ctnt ( ) ( )

4 ng/l ( ) (1) Adjusted for age 76 years, gender, stroke severity (NIHSS), CHD, CVD, congestive heart failure, rt-pa, atrial fibrillation, smoking, hypertension, hyperlipidemia, diabetes mellitus, blood leukocyte count, egfr

5 Reviewer 2 1. Still, the difference between patients diagnosed with AMI during the hospital stay (n=15) and patients enrolled to the study with elevated ctn and ECG alterations does not become clear. Which criteria were applied for referring patients to cardiologists? Reply: The patients diagnosed with AMI were excluded, thus the patients fulfilling AMI criteria in this study were undiagnosed patients. The decision to refer patients to a cardiologist was made by the treating neurologist based on the available information (past medical history, clinical evaluation, results from blood samples and ECGs). Because of the retrospective nature of the present study it was not possible to conduct the study otherwise. However, we are planning a prospective study on troponin elevation in acute ischemic stroke, and we will include specific criteria for referring patients to a cardiologist. 2. The conclusions regarding dynamic change of ctn are still not supported by the data. Because of the low event rate, the results of the multiple regression analysis should not be presented (following the rule of ten - one covariate per 10 outcomes the multiple regression analysis does not make sense). Because of the different observation period only results of a univariate cox regression analysis should be presented. Since several factors associated with mortality (older age, NIHSS and atrial fibrillation just to name a few) are associated with ctn, even the univariate results should be interpreted with caution. It remains questionable whether the findings are a suitable focus of the manuscript. The conclusion section of the abstract and discussion need further revision. Reply: We agree that too many variables were included in the multivariate analysis regarding dynamic change and in-hospital mortality, given the low event rate. In this revision, we have reduced the number of variables in the analysis (excluded congestive heart failure (correlation to coronary heart disease), tr-pa, hyperlipidemia and blood leukocyte count). Because we were interested in in-hospital mortality independent of hospital stay, we have used logistic regression analyses (and not Cox-regression), Table 4: p value Unadjusted OR (95% CI) P value Adjusted OR (95% CI) (1) hs-ctnt > 14 ng/l ( ) ( ) 1.15 ( ) log hs-ctnt ( ) ( ) 1.21 ( ) δ hs-ctnt 20% ( ) ( ) δ hs-ctnt 20% ( ) ( ) 5.35 ( ) δ hs-ctnt ( ) ( ) ng/l δ hs-ctnt 9.2 ng/l ( ) ( ) 4.77 ( ) (1) Adjusted for age 76 years, gender, stroke severity (NIHSS), CHD, CVD, congestive heart failure, rt-pa, atrial fibrillation, smoking, hypertension, hyperlipidemia, diabetes mellitus, blood leukocyte count, egfr

6 In the discussion, the text regarding short-term prognosis is revised: (..) which may indicate that dynamic changes in troponin levels rather than stable elevation related to chronic diseases are could be related to poor short-term prognosis. The results also indicate that dynamic changes could be of relevance in other clinical settings in addition to acute coronary syndrome, such as cerebrovascular disease. ( )Second, there was a variation in time between the two hs-ctnt measurements, and the results regarding dynamic changes should therefore be interpreted with caution. In addition, because of the relatively low number in-hospital mortality events, the results from the multivariate analyses should be considered preliminary, and larger studies are needed to clarify this issue.

7 Reviewer 3 After all changes made by authors I am satisfied with quality of the manuscript and I consider it to be suitable for publication. I recommend it.

8 Reviewer 4 1. Table 4: According to the universal Definition of MI only patients fulfilling (3) criteria have acute myocardial injury, but patients with kinetics without increase >99th percentile do not. Lines labelled with should be deleted from the table. Reply: We agree that rise or fall without an increase > 99th percentile is not that relevant or interesting, and therefore removed it from table 4. p value Unadjusted OR (95% CI) P value Adjusted OR (95% CI) (1) hs-ctnt > 14 ng/l ( ) ( ) log hs-ctnt ( ) ( ) δ hs-ctnt 20% ( ) ( ) δ hs-ctnt 20% ( ) ( ) δ hs-ctnt 9.2 ng/l ( ) ( ) δ hs-ctnt 9.2 ng/l ( ) ( ) (1) Adjusted for age 76 years, gender, stroke severity (NIHSS), CHD, CVD, congestive heart failure, rt-pa, atrial fibrillation, smoking, hypertension, hyperlipidemia, diabetes mellitus, blood leukocyte count, egfr Rise or fall Rise or fall with at least one value above the 99 th percentile of the upper reference limit (> 14 ng/l) 2. Reference 26 is incomplete. Reply: Thank you for spotting this error, which is corrected in the revised manuscript. 26. Furtner M, Ploner TF, Hammerer-Lercher AF, Pechlaner RF, Mair J: The highsensitivity cardiac troponin T assay is superior to its previous assay generation for prediction of 90-day clinical outcome in ischemic stroke. Clin Chem Lab Med 2012, 50:

9 Reviewer 5 1. At the end of the abstract, what are type 1 or type 2 MI? Reply: Myocardial infarction type 1-5 are included in the third universal definition of myocardial infarction (Thygesen et al, Third universal definition of myocardial infarction, Eur Heart J 2012;33: ). Type 1: Spontaneous myocardial infarction; type 2: Myocardial infarction secondary to an ischemic imbalance. As mentioned by Reviewer 1 expressions such MI type 1 or type 2 should be avoided in the abstract (too specific), we have removed this from the abstract. 2. The end of the introduction would be better if there was one good and quantified original hypothesis, not four vague aims. Reply: We have rephrased the last part of the introduction: The aims of the present study were to assess the frequency of high sensitivity cardiac troponin T (hs-ctnt) elevation, to identify possible determinants associated with high sensitivity cardiac troponin T (hs-ctnt) elevation and to determine the prevalence of ECG changes in patients with acute ischemic stroke., and to identify ECG changes associated with hs-ctnt elevation. In addition, we wanted to examine whether hsctnt values on admission or dynamic changes in hs-ctnt are related to in-hospital mortality. 3. The stats section lacks any mention of power. Are the authors convinced their sample size is big enoujgh for all these indices? It is unclear why a perfectly good continously variable index like age should be dichotomised. The same is, of course, true for TnT but I do see the point of a cut-off value for this marker. Reply: Thank you for these remarks. A power calculation was not performed in this retrospective study, and we chose to include patients admitted during one year. However, we are planning a prospective study on troponin elevation in acute ischemic stroke in which a strict power calculation will be performed. We agree that age is a good continuously variable, but opted to dichotomize it at the end. The reason to dichotomize age was to make the results more relevant in a clinical setting (a cut-off age rather than higher age ). The same applies to hs-ctnt. 4. There is considerable duplication of data in the text and in the tables. Once only please. Reply: Thank you for this comment. In the revised manuscript, we have removed some text: A higher proportion of patients with hs-ctnt 14 ng/l were treated with rt-pa (p<0.001). There were no significant differences regarding pulse and BP. Regarding stroke subtypes, patients with elevated hs-ctnt had significantly higher frequency of cardioembolic strokes (p<0.001). In addition, they had longer PR interval (p=0.005), QRS duration (p=0.010) and QTc interval (p=0.010)

10 5. There needs to be an explanation for the marked sex difference in AF and DM versus TnT (table 3). Reply: Thank you for this interesting remark. Because of the retrospective nature of the study and limited data, we have not discussed the sex difference in the discussion. Indeed, males seem to have a more coronary profile (coronary heart disease, heart failure, AFli) than females. We hope to address this topic in our planned prospective study.