The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy–VISTA-Endovascular

Anna Kufner; Huma Fatima Ali; Martin Ebinger; Jochen B. Fiebach; David S. Liebeskind; Matthias Endres; Bob Siegerink; on behalf of the VISTA-Endovascular Collaborators

doi:10.1371/journal.pone.0251888

Peer Review History

Original SubmissionJanuary 25, 2021
2 Mar 2021 Decision Letter - Miguel A. Barboza, Editor PONE-D-21-02613 The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy - VISTA-Endovascular PLOS ONE Dear Dr. Kufner, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. There are some few concerns, related methodological issues that should be acknowledged, and also some limitations and bias from your study that also should be explained, mainly in comments from reviewer 1; I suggest to take a careful look at this suggestions. Please submit your revised manuscript by Apr 16 2021 11:59PM. 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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 4.Thank you for stating the following in the Competing Interests section: "AK, HFA, M. Ebinger, and BS report not disclosures. JBF reports consulting and advisory board fees from Abbvie, AC Immune, Artemida, BioClinica, Biogen, BMS, Brainomix, Cerevast, Daiichi-Sankyo, EISAI, Guerbet, Ionis Pharmaceuticals, Julius Clinical, jung diagnostics, Eli Lilly, Merck, and Tau Rx, all outside of the submitted work. M. Endres reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, and Novartis, all outside of the submitted work. DSL reports research funding as an imaging core lab from Cerenovus, Genentech, Medtronic and Stryker." 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In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 7. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 8. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you to the authors for submitting the current paper: “The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy”. Active smoking is one of the most modifiable cardiovascular risk factors. Sick people with several ongoing cardiovascular and metabolic diseases (CHF, coronary artery disease and diabetes) tend to quit smoking (perhaps the exemption being peripheral arterial disease). Observational studies pointed a possible “beneficial” effect of smoking in subjects with AIS that underwent to IV r-tPA. Almost half of your subjects underwent to EVT and in that group 216 subjects (60 smokers and 156 nonsmokers) underwent to infusion of IA thrombolytics as adjunct treatment to the MT and non-smoker subjects carried more burden of diseases CHF, diabetes y coronary artery disease. This burden of diseases represents an important confounder factor in the outcome (including degree of disability and mortality). I have a couple of concerns/remarks: 1. Why BMI/Baseline mRS was not reported? This are factors that definitively influence the outcome. 2. Why do think that a deleterious substance like tobacco/nicotine/tar would have a protective effect. This is when statistics pitfall might mislead biological effects/interactions. 3. Observation studies pointed smokers might face a better outcome after exposed to IV r-tPA but we know that they are exposed to an standard doses (0.9 mg/Kg max 90 mg) but here there is no information about what IA doses was used. 4. The introduction is longer than accepted. The discussion is excessively and unnecessarily long. Discussion should not be more than 4-6 paragraphs (no more than 1-2 pages). Many of the proposed mechanism are merely speculations. It is hard for the reader to keep up with so many tables and smoker-nonsmoker comparisons. In the methods section, the VISTA data base can be referred and shorten its description. Reviewer #2: I WOULD LIKE TO SEE SOME GRAPHICAL REPRESENTATION OF RELATIVE RISK AND CONFIDENCE INTERVALS PRESENTED IN THE STUDY, THE STUDY INCLUDES MANY DATA WITH THIS FORMAT THAT COUL BE MORE EASILY INTERPRETED IN A GRAPHICAL WAY ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Alberto Maud Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0251888.r001
Revision 1
26 Mar 2021 Author Response RESPONSE TO THE REVEIWERS – PLOS ONE R1 Reviewer #1: Thank you to the authors for submitting the current paper: “The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy”. Active smoking is one of the most modifiable cardiovascular risk factors. Sick people with several ongoing cardiovascular and metabolic diseases (CHF, coronary artery disease and diabetes) tend to quit smoking (perhaps the exemption being peripheral arterial disease). Observational studies pointed a possible “beneficial” effect of smoking in subjects with AIS that underwent to IV r-tPA. Almost half of your subjects underwent to EVT and in that group 216 subjects (60 smokers and 156 nonsmokers) underwent to infusion of IA thrombolytics as adjunct treatment to the MT and non-smoker subjects carried more burden of diseases CHF, diabetes y coronary artery disease. This burden of diseases represents an important confounder factor in the outcome (including degree of disability and mortality). I have a couple of concerns/remarks: RESPONSE: Thank you very much for taking the time to review our manuscript. R1: Why BMI/Baseline mRS was not reported? This are factors that definitively influence the outcome. RESPONSE: The reviewer correctly points out that additional factors including BMI as well as baseline mRS may influence outcome. We contacted the VISTA-Endovascular Research Group and requested these additional clinical parameters. Unfortunately, as the clinical data used in this study stems from numerous differing randomized-controlled trials, these variables are not commonly available and are therefore not included in the VISTA-Endovascular dataset. We have now expanded the following sentence in our limitation section on page 13: “...other potentially relevant clinical parameters (such as body-mass-index and pre-stroke mRS) also could not be adjusted for as these parameters were not commonly available. The latter is a limitation inherent to our study design, in which data was analyzed from pooled trial data not primarily designed to address our research question.” – Page 13 R2: Why do think that a deleterious substance like tobacco/nicotine/tar would have a protective effect. This is when statistics pitfall might mislead biological effects/interactions. RESPONSE: This is an important point that the reviewer brings up that certainly warrants discussion. We can be almost certain from what we know from pre-clinical studies and our clinical experience that there is no direct biological protective effect from tobacco smoke. There are dozens of known deleterious substances in tobacco smoke that have well-known detrimental effects on the organism as a whole. Therefore, any potential observed “beneficial” effect of smoking on stroke outcome, can only be termed a paradox –smoking is a well-known, and highly relevant risk factor for stroke and other cardiovascular diseases. The described studies that observe the so-called “smokers-paradox” in treated stroke patients hypothesize that either 1) smokers tend to be younger when they have a stroke but then respond better to thrombolytic treatment due to changes in the clot-composition (which also make’s them more susceptible to stroke) or 2) smokers have such poor artherosclorotic plaques which causes long-term collateral-formation due to chronic ischemia and hence tissue is held viable before reperfusion is achieved post-stroke (as opposed to non-smokers who have higher rates of cardio-embolic stroke). In other words, there is no direct beneficial effect of tobacco smoke and/or the deleterious substances in cigarettes – rather, it is certainly detrimental to the health and a strong risk factor for cardiovascular diseases. This is the focus of our introduction. To conclude and to quote the conclusion of our original smoking-paradox paper (Kufner et al. 2013 Stroke): “no stroke is always better than a recanalized stroke.” To emphasize that we by no means encourage smoking, we have now added the following sentence to our Summary/Conclusions section on page 13-14 to avoid any misunderstandings from our readers: “Needless to say, smoking has well-known detrimental effects on the cardiovascular system and should be by no means encouraged.”- Page 13-14 R3: Observation studies pointed smokers might face a better outcome after exposed to IV r-tPA but we know that they are exposed to an standard doses (0.9 mg/Kg max 90 mg) but here there is no information about what IA doses was used. RESPONSE: The reviewer correctly points out that information on IA-tPA dosages given would be a valuable parameter to assess in this analysis. We have contacted the VISTA-Research Group and unfortunately this data is not available. We have now adjusted the following sentence in our limitations section to account for this important point: “Further limitations of this study include missing data relevant to our research question i.e. type of smoking habits (i.e. type of tobacco consumption, pack years etc.) and IA-thrombolysis d bosages to assess possible dose-effect on treatment efficacy, as well as stroke etiology to adjust for when assessing collateral status between smokers and non-smokers... the latter is a limitation inherent to our study design, in which data was analyzed from pooled trial data not primarily designed to address our research question.” – Page 14 R4: The introduction is longer than accepted. The discussion is excessively and unnecessarily long. Discussion should not be more than 4-6 paragraphs (no more than 1-2 pages). Many of the proposed mechanism are merely speculations. It is hard for the reader to keep up with so many tables and smoker-nonsmoker comparisons. In the methods section, the VISTA data base can be referred and shorten its description. RESPONSE: The reviewer makes a valid point and requests we shorten parts of the manuscript and to emphasize/focus on relevant results. This manuscript has circulated not only to our co-authors, but also to the entire Steering Committee of the VISTA-Endovascular Research Group; we tried to incorporate everyone’s suggestions and ideas, which surely played a role in lengthiness of the article. We have now, however, revisited parts of the manuscript and have greatly shortened the introduction, methods, and discussion. Thank you for this comment. We believe the shortening of the text, as suggested by the reviewer, has improved the manuscript and makes it easier for the readers to follow. Reviewer #2: I WOULD LIKE TO SEE SOME GRAPHICAL REPRESENTATION OF RELATIVE RISK AND CONFIDENCE INTERVALS PRESENTED IN THE STUDY, THE STUDY INCLUDES MANY DATA WITH THIS FORMAT THAT COUL BE MORE EASILY INTERPRETED IN A GRAPHICAL WAY RESPONSE: Thank you for taking the time to review our manuscript. We very much like the reviewer’s suggestion and agree that presenting the reported RRs with CIs in a graphical manner is very helpful for the readers. We have now completely replaced Table 3 and Table 4 with graphics (now called Figure 1 and Figure 2), and moved these tables into the supplemental files. In the process, we actually noticed an important error in our Table 3 analysis and are very thankful to the reviewer for bringing up the figures, which ultimately led to this discovery. We noticed that almost exclusively patients who received MT+IAT or “standard medical treatment” (i.e. no endovascular therapy) have missing information on arterial occlusion (AO). On the one hand, this was the reason for why we chose to exclude AO from adjusted analyses in patients with MT+IAT (as reported in Table 3, last section); but we didn’t account for the fact that in adjusted analyses for outcome endpoints in “all patients” (Table 3, first section), almost exclusively MT-only patients would be included in adjusted analyses (patients with missing values for AO were kicked out = all patients with MT+IAT or no EVT). This is of course relevant for this type of analysis, which we failed to notice. Fortunately, our results do not change materially and therefore our original conclusions still hold. However, we acknowledge that we cannot adjust for AO when comparing outcome endpoints based on mode of therapy as we did in Table 3 because the parameter itself is reported in a biased manner. We apologize for overlooking this important detail and are grateful to the reviewer for bringing up this point. We now added the requested figures of RR and CI’s, adjusted parts of the text as necessary (references to the new tables and figures), and added the following to our limitations section in the discussion: “...potentially relevant clinical parameters (such as body-mass-index, pre- stroke mRS, and site of arterial occlusion) also could not be adjusted for as these parameters were not commonly available. The latter is a limitation inherent to our study design, in which data was analyzed from pooled trial data not primarily designed to address our research question." – Page 13 Attachments Attachment Submitted filename: renamed_690b5.docx https://doi.org/10.1371/journal.pone.0251888.r002
5 May 2021 Decision Letter - Miguel A. Barboza, Editor The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy - VISTA-Endovascular PONE-D-21-02613R1 Dear Dr. Kufner, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Miguel A. Barboza, MD, MSc Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0251888.r003
Formally Accepted
10 May 2021 Acceptance Letter - Miguel A. Barboza, Editor PONE-D-21-02613R1 The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy–VISTA-Endovascular Dear Dr. Kufner: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Miguel A. Barboza Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251888.r004

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