Guidelines recommend stepping down asthma treatment to the minimum effective dose to achieve symptom control, prevent adverse side effects, and reduce costs. Limited data exist on asthma prescription patterns in a real-world setting. We aimed to evaluate the appropriateness of doses prescribed to a UK general asthma population and assess whether stepping down medication increased exacerbations or reliever use, as well as its impact on costs.We used nationwide UK primary care medical records, 2001–2017, to identify 508,459 adult asthma patients managed with preventer medication. Prescriptions of higher-level medication: medium/high-dose inhaled corticosteroids (ICSs) or ICSs + add-on medication  steadily increased over time . Of those prescribed their first preventer, one-third were prescribed a higher-level medication, of whom half had no reliever prescription or exacerbation in the year prior. Of patients first prescribed ICSs + 1 add-on, 70.4% remained on the same medication during a mean follow-up of 6.6 years. Of those prescribed medium/high-dose ICSs as their first preventer, 13.0% already had documented diabetes, cataracts, glaucoma, or osteopenia/osteoporosis. A cohort of 125,341 patients were drawn to assess the impact of stepping down medication: mean age 50.4 years, 39.4% males, 39,881 stepped down. Exposed patients were stepped down by dropping their LABAs or another add-on or by halving their ICS dose . The primary and secondary outcomes were, respectively, exacerbations and an increase in reliever prescriptions. Multivariable regression was used to assess outcomes and determine the prognostic factors for initiating stepdown. There was no increased exacerbation risk for each possible medication stepdown  and no increase in reliever prescriptions . Prognostic factors to initiate stepdown included medication burden, but not medication side effects. National Health Service (NHS) indicative prices were used for cost estimates. Stepping down medication, either LABAs or ICSs, could save annually around £17,000,000 or £8,600,000, respectively. Study limitations include the possibility that prescribed medication may not have been dispensed or adhered to and the reason for stepdown was not documented.In this UK study, we observed that asthma patients were increasingly prescribed higher levels of treatment, often without clear clinical indication for such high doses. Stepping down medication did not adversely affect outcomes and was associated with substantial cost savings. Chloe Bloom and co-workers analyze data on stepping down asthma medications in UK patients. There is a growing interest in rationalising medicines through deprescribing.Specifically, asthma guidelines strongly recommend stepping down asthma medication in stable patients to reduce the risk of side effects from long-term use, in particular from inhaled corticosteroid use.Guideline recommendations are based on trials, comparing stable patients that were stepped down to those that were not, but these trials were small in size, had short follow-up periods, and may not represent what happens in day-to-day clinical practice.We studied adult asthma patients from across the UK, using primary care electronic medical records, and found prescriptions of higher-dose asthma medication have steadily increased between 2001 and 2017.Stepping down medication occurred infrequently but did not increase asthma exacerbations or the use of reliever medication; patients at risk of medication side effects were not preferentially stepped down.This clinical practice was shown to have considerable cost savings if carried out in stable asthma patients.There is an increasing tendency to prescribe higher-dose, expensive asthma medications.Stepping down was found to be safe and highly cost-effective and may reduce long-term medication adverse effects. Over the past 4 decades, the use of inhaled corticosteroids (ICSs) and, subsequently, long-acting β2-agonists (LABAs) have resulted in extraordinary improvements in outcomes for people with asthma ,2. SinceThe GINA 2019 guidelines recommend a paradigm shift in asthma treatment, advising all asthma patients to receive ICSs, starting with low-dose ICSs or as-needed low-dose ICS–formoterol in the GINA guidelines, and escalating as necessary. For the majority of patients, 80%–90% of the therapeutic benefit of ICSs are obtained with low doses . ProlongIn this study, using nationally representative primary care data from across the UK, we first evaluated the temporal pattern of preventer prescriptions , the associated patient characteristics, and the frequency of medication step change. We then focused on patients that were stepped down to evaluate any associated health and cost impact.The protocol for this research was approved by the Independent Scientific Advisory Committee (ISAC) for MHRA Database Research (protocol number 18_120) and is available alongside the STROBE checklist for observational studies . This stWe used the CPRD-GOLD, a nationally representative database of deidentified UK primary care electronic medical records. CPRD holds information on diagnoses, symptoms, and prescriptions on more than 11 million patients . It is oIn the UK, each single inhaler prescribed should last one month if taken as per manufacturer intended dose . A new prescription is recorded for every successive inhaler, and more than one of the same inhaler can be prescribed on the same day (and is recorded as such).st, 2001, research acceptable date , continuous records date, 18th birthday, or asthma diagnosis date. Follow-up was censored at the earliest date of the following: January 1st, 2018, date transferred out of CPRD, last data collection, or death.Inclusion criteria were an asthma diagnosis using a validated algorithm of including asthma clinical codes  , no chroTo be eligible, patients had to have ≥1 year of follow-up and ≥3 preventer prescriptions Figs . For theTo determine the health impact, a cohort of regular preventer users was drawn from the main study population  & S1 FigThe ‘index date’ for the outcome analysis was then recorded as 2 months from the stepdown date. This time period was set because although a single inhaler prescription should last 1 month, many patients miss doses. In this cohort, patients received a mean of 7 prescriptions per year (IQR 6–9), suggesting each inhaler was used on average for approximately 2 months. Therefore, after this time period, patients were considered to be no longer using their dropped medication; however, a sensitivity analysis was also carried out assuming 1- and 3-month time periods.Stepping down was based on guideline recommendations and was defined as (1) dropping an add-on therapy , (2) halving the ICS inhaler dose , or 3) halving the mean-daily ICS dose   halving . Most ICA drop in mean-daily ICS was measured by comparing the mean ICS dose per day in 1 year with the mean ICS dose per day in the first 4 months of the subsequent year (‘assessment year’). The first day of the assessment year was recorded as the index date.Escalation was defined as the opposite of stepping down  occurring in the year following the index date.The primary outcome was asthma exacerbations. These were identified as previously defined , as a shFor prevalent prescriptions, the maximum therapy level per patient each calendar year was determined. To evaluate change in prescriptions from the first (incident) preventer medication prescribed, a single prescription increase/decrease during a patient’s total follow-up was recorded as a change. The effect of stepping down on exacerbations was analysed in an intention-to-treat Cox proportional hazards model adjusted for sex, age, body mass index (BMI), smoking, socioeconomic class, gastroesophageal reflux, anxiety, depression, annual asthma review, inhaler technique check, asthma management plan, exacerbations, reliever use, maximum ICS dose, ICS frequency, ICS stability, and add-on therapies using complete case analysis. Patients were censored on their first exacerbation or 1 year after the index date. Schoenfeld residuals were found not to violate the proportional hazards assumption . The effCost analyses for the cohort were performed applying drug costs alone. Price per drug was obtained using 2019 indicative prices from the NHS Dictionary of Medicines and Devices to avoid a cost effect due to price changes . Patient508,459 patients were identified; the proportion on higher-level preventer medications (medium/high-dose ICSs or ICSs and add-on therapy) steadily increased over time , 48.4% had no exacerbation or reliever prescriptions in the previous year. The median time since diagnosis before first prescription was 19.2 months, and 13.2% already had a comorbidity that could be worsened by corticosteroids .Of those prescribed medium- or high-dose ICSs as their incident prescription, 13.0% had known diabetes, cataracts, glaucoma, osteopenia, or osteoporosis at the time of prescription, compared with 11.2% prescribed incident low-dose ICSs .125,341 patients  satisfied the criteria for the stepping-down analysis: 39,881 were stepped down , and 85,460 were not stepped down .Stepping down LABA or other add-on medication or ICSs, either by reducing the dose of the inhaler or by reducing the number of puffs, did not significantly increase the risk of an exacerbation in the subsequent year , In a representative UK general asthma cohort, we have shown that between 2001 and 2017, prescription of higher-level preventer medications became increasingly common. There was often no clear clinical requirement for such high doses; one-third of patients had not received a reliever inhaler prior to their first asthma prescription or had an exacerbation. Nearly three-quarters of patients who were prescribed an ICS + 1 add-on as their first medication remained on the same medication for several years. One in 8 patients who were prescribed a medium/high-dose ICS as their first preventer already had known steroid-induced adverse effects. When medication stepdown was initiated, it was found to be safe, with no increase in exacerbations or reliever use, and economical.In over 0.5 million asthma patients, the proportion prescribed higher-level medications  steadily increased over the past 2 decades. By 2017, only one-third of patients were managed on low-dose ICSs alone, in keeping with older UK studies also suggestive of inappropriate prescribing of higher doses of ICSs ,29. ThisPhysicians prescribing higher ICS doses were perhaps also not alert to potential adverse systemic effects because 13% of those prescribed medium- or high-dose ICSs as their first prescription already had known relevant comorbid conditions  compared with 11% of those prescribed low-dose ICSs. The majority of patients prescribed ICSs and an add-on were prescribed a fixed daily medium-dose or high-dose ICS–LABA combination inhaler. The latest recommendation in GINA for mild and moderate asthma, supported by multiple recent randomised control trials (RCTs) –38, is aThe most common form of stepdown was halving ICS inhalations, a pragmatic approach that can be readily instigated by patients with or without direction from healthcare professionals. Stepdown did not significantly increase the risk of exacerbations, regardless of which medication was stepped down. Interestingly, there was a slight reduction in exacerbations when stepping down ICSs not seen when stepping down add-on therapies. This could be explained by confounding by indication from an unmeasured variable that led to patient selection only in patients with ICS overtreatment or could be due to increased adherence after medication change from increased medication awareness .Findings remained robust even after all sensitivity analyses. As may be expected, the biggest positive confounding effect was a history of exacerbations in the year prior , but eveA Cochrane Review, 2017, looked at studies that stepped down ICSs in well-controlled asthma patients . The revThere has only been one previous real-world study comparing stepped-down patients to controls. Using US administrative claims data, the authors identified a smaller cohort of 4,235 eligible patients with a shorter follow-up period and no exact timing of stepdown; this study found stepping down to be safe and highly cost-effective .Around 1 in 6 controls had their treatment escalated in the year after the index date; this number was comparable to those that stepped down their ICS inhalations or their LABAs. A slightly higher number, around 1 in 5, escalated treatment if they had dropped LTRAs, LAMAs, or the ICS inhaler dose. Stepping down did not significantly increase the use of reliever medication, and most patients did not escalate treatment more than the controls; together, these findings suggest stepping down did not have a detrimental effect on patient’s asthma control.Although the reason for stepping down was not recorded, we were able to evaluate several potential prognostic factors. We found higher levels of medication and prescription stability were associated with instigating stepping down. Use of combination inhalers was associated with reduced odds of stepping down ICSs; however, this is likely to change with the latest GINA guidelines encouraging an as-needed approach. In contrast, common ICS adverse systemic effects, diabetes, cataracts, glaucoma, osteopenia, or osteoporosis were not associated with stepping down ICS. Older age was significantly associated with not having ICSs stepped down but was significantly associated with stepping down LABAs. Yet the older population are at the greatest risk of ICS side effects and are most likely to experience polypharmacy. In the UK, older people have a similar prevalence of asthma as younger adults but are the age group most likely to be prescribed ICSs and most likely to be prescribed medium- or high-dose ICSs instead . It seemOur cost analysis found considerable savings covering during just 1 year. The savings from dropping LABAs were almost 4 times that of ICSs and approximately double that of LTRAs. Scaling up the costs to estimate nationwide savings, assuming only half of all stable treated patients are stepped down, could potentially save around £17 million if LABAs were stepped down, equivalent to 2% of the UK’s asthma budget, or £8.6 million if ICSs were stepped down. This large sum is because over 5.4 million people receive asthma treatment in the UK, with asthma medication contributing towards 13% of the total primary care prescribing costs  and ICSsMajor strengths were the use of a nationally representative study population, large sample size, and longevity of the data. Limitations of using routinely collected patient data include lack of information on daily medication use; therefore, to include patients who reduced the number of puffs, we had to calculate mean-daily ICS doses. This could have led to selection bias by excluding patients who decreased, then increased, their puffs again. However, our findings in this group were consistent with patients that had their ICS inhaler dose halved, suggesting this bias had a minimal influence on the effect estimate. It is possible there was selection bias from only including HES-linked patients in the stepping-down analysis because HES is only available for patients using English NHS hospitals. The nature of the data also did not allow us to know precisely why the decision to initiate stepdown was taken; hence, our analysis of potential prognostic factors attempted to investigate this. Although the algorithm used to identify asthma patients has 86% positive predictive value , a limitOver time, patients in the UK have been increasingly prescribed higher-level asthma medications with no clear clinical indication for needing higher doses. Worryingly, although stepping down of treatment is recommended by clinical guidelines, we found that it happened infrequently. Stepping down ICSs or add-on therapy did not appear to worsen health outcomes but did appear to result in significant cost savings. Medication burden seemed to be the main driver to stepping down; adverse medication effects were not. In summary, firstly, adverse treatment effects, medication burden, and cost to the health system should be considered when prescribing higher-level asthma medications for well-controlled asthma patients seen in primary care. Secondly, stepping down medication in stable asthma patients appears to be both safe and highly cost-effective.S1 STROBE Checklist(DOCX)Click here for additional data file.S1 TableICS, inhaled corticosteroid(XLSX)Click here for additional data file.S2 TableSensitivity analysis, risk of exacerbation after stepdown (a) using a 6-month outcome window (instead of 12 months), (b) using a definition of stepping down starting 1 month or 3 months after the last prescription containing the stepped-down drug, (c) using an as-treated approach.(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 TableOnly factors significantly associated (p < 0.05) with initiating stepdown are shown (OR > 1); each variable is adjusted for all variables in the model. The effect estimate shown is the adjusted odds ratio as compared to their reference value. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.(XLSX)Click here for additional data file.S7 TableNHS, National Health Service(XLSX)Click here for additional data file.S1 FigAdd-on therapy refers to LABA, LTRA, theophylline, or LAMA. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist(TIF)Click here for additional data file.S1 Study Protocol(DOC)Click here for additional data file.S1 CPRD medcodesCPRD, Clinical Practice Research Datalink(PDF)Click here for additional data file. 10 Jan 2020Dear Dr Bloom, Thank you for submitting your manuscript entitled "Health and cost impact of stepping-down asthma medication: a UK population-based observational study" for consideration by PLOS Medicine.Your manuscript has now been evaluated by the PLOS Medicine editorial staff [as well as by an academic editor with relevant expertise] and I am writing to let you know that we would like to send your submission out for external peer review.However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. 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Thank you for your patience.**plosmedicine@plos.org if you have any queries relating to your submission.Feel free to email us at Kind regards,Caitlin Moyer, Ph.D.Associate EditorPLOS Medicine 16 Mar 2020Dear Dr. Bloom,Thank you very much for submitting your manuscript "Health and cost impact of stepping-down asthma medication: a UK population-based observational study" (PMEDICINE-D-20-00031R1) for consideration at PLOS Medicine. Your paper was evaluated by an academic editor with relevant expertise and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:[LINK]In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that fully addresses the reviewers' and editors' comments. 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For such statements, authors must provide supporting data or cite public sources that include it. Please ensure that the paper adheres to the PLOS Data Availability Policy  and, if so, attach the document(s) as a supplementary file, referred to in the text. Please highlight analyses that were not prespecified. Please restructure the early part of your discussion section so that the first paragraph provides a summary of the study's findings. Please make that "include" at line 370. Throughout the paper, please quote exact p values or "p<0.001".Throughout the text, please format reference call-outs as follows: "... people with asthma .".In your reference list, please remove the academic editor's name from reference 4. Please attach a completed checklist for the most appropriate reporting guideline, which may be STROBE, as a supplementary document (referred to in your methods section). In the checklist, please refer to individual items by section  and paragraph number rather than by line or page numbers, as the latter general change in the event of publication. Comments from the reviewers:*** Reviewer #1: "Health and cost impact of stepping-down asthma medication: a UK population-based observational study" finds that asthma patients were bring prescribed higher levels of treatment oft without clear clinical indications, from nationwide UK primary care medical records from 2001 to 2017. Further analysis concluded that stepping-down medication to the minimum effective dose did not adversely affect outcomes, and moreover saved on costs. Indeed, stepping-down of ICS in particular consistently reduced hazard ratios (Tables S2/S3).A major strength of this study would lie in the large number of patients involved , from a cohort of over 500,000 patients from the UK primary care system over 17 years. Findings on the efficacy of stepping-down remained largely unchanged under relevant sensitivity analyses. To the best of our knowledge, there exists no prior study of comparable scale on the impacts of stepping-down asthma medication. Therefore, this study may have significant potential to affect health policy on asthma management, especially with an observed increase in the prescription of higher level medication, and purported insufficient evidence about stepping-down ICS medication as a factor in increased risk of future asthma attacks (e.g. from page 33 of the BTS/SIGN 2019 guidelines).There however remain some points that might be clarified:1. In lines 62-64, The appropriate citations might be provided for the various asthma guidelines 2. From line 126, how was the criteria of >= 3 ICS prescriptions  decided upon, given the mean of 7 prescriptions per year (line 133)? Data on the distribution of prescriptions/year might be illuminating.3. On the definition of "stepping-down" (Line 138 onwards) - some possible configurations of medication step-down appear not to be explicitly covered by the chosen definition. For example, in prior work : 70-75.), it is claimed that "certain step-down practices such as the complete cessation of ICS to LABA alone was associated with a significant loss of asthma control". How might dropping ICS to an add-on therapy be categorized in the analysis (e.g. in Table 4 & 5)?4. More generally, how were the stepping-down definitions decided? Is halving dosage, for example, universally accepted practice as opposed to say a reduction of dosage by 25% ? 5. The incidence rate (N) for the various drug-stepped-down categories might be provided in Tables 4 & 5, for convenience.6. The definition of reliever prescriptions as a secondary outcome (e.g. line 154) might not be entirely obvious. The authors might consider adding a short description of preventer/reliever usage practices in the Introduction. Further, what is the tradeoff between reduced preventer and increased reliever usage?7. On the incident analysis, it was stated that (line 229) "Of those prescribed higher level medication as their incident asthma prescription... 48.4% had not excerbation or reliever prescriptions in the previous year (Table 2)"; however, the 48.4% figure is not immediately evident from the presentation of Table 2.8. Moreover, the authors might consider standardizing the formatting of Tables 2/S1/S4 (i.e. consistently place "N" and "%" as separate columns), and include p-values where appropriate.9. The characteristics examined for incident vs. step-down analysis (i.e. Table 2 vs. Table 3) are fairly different; for instance, age and socioeconomic status are not considered in the incident analysis, although it is not obvious that they do not affect/correlate with incident prescriptions. The authors might consider briefly discussing the selection of characteristics for each analysis.10. In line 236, it is stated that "(of) 125,341 patients, 39,897 were stepped-down, and 85,460 were not stepped down". However, the sum of stepped-down and non-stepped-down patients appears to be 125,357 patients.11. Also, from the definition of stepping-down and the chronological length of the study (17 years), it seems possible that an individual (exposed) patient might step-down  medication multiple times, over the full time period. How are such cases, if any, accounted for?12. From line 292, "Our study found most patients receiving a higher level preventer medication as their first asthma medication had not received a prescription for a preventer inhaler in the previous year )", is "preventer medication" not considered "preventer therapy"?13. In line 310, it is mentioned that step-down can be instigated by patients, possibly without direction from healthcare professionals. How does this happen in practice? Moreover, for the prescription data used in the analyses, were they taken as prescribed by the primary care health professionals (i.e. possibly not followed up on), or as filled by pharmacists?14. In line 355, which two studies do "both studies" refer to?15. The discussion on prior investigations on medication step-down for asthma may be somewhat perfunctory. For example, it is claimed that (line 328) "Several randomised controlled trials of medication step-down have shown no difference in asthma exacerbations, asthma control, side-effects or quality of life"; however, citation (36) alone mentions that "Of 14 randomized controlled studies on step down of asthma medications , only 4 of them found no significant differences in asthma outcomes compared with patients maintaining their asthma medications". Therefore, while there appears to be a general consensus from the latest asthma management guidelines on stepping-down controlled asthma cases to a minimal level, the evidence from previous randomized controlled trials appears somewhat mixed, even considering recognized methodological limitations. The authors might consider commenting in greater depth on these previous studies.16. Finally, there may be some minor grammatical issues, e.g.Line 39: "A cohort of patients were drawn..." -> "was drawn"Line 47: "...and no increased in reliever" -> "no increase"Line 297: "Perhaps not a surprising finding..." -> "This is perhaps not a surprising finding..."Line 337: "this number was comparative..." -> "was comparable"?*** Reviewer #2: This is an excellent study showing that asthma patients in the UK (1) are often initiated on overly intensive therapy, (2) are kept on intensive therapy without attempts to step down (contra guidelines), and (3) have no better outcomes than those whose therapy is stepped down.Major1. My biggest concern is with the third finding—that stepping down therapy was not associated with more exacerbations or SABA use than continuation of therapy. As the authors recognize, there is a strong possibility for selection bias. They perform a stratified analysis based on exacerbations in the prior year. They also report in Tables 4 and 5 regression analyses that control for a number of potential confounders. These steps all help address the worry of unmeasured confounding. However, they did not perform the analysis with propensity score matching , which may help further allay concerns. In general, I worry that the group whose therapy was stepped down is different in important ways than the group whose therapy was continued.2. The authors did not report on any difference in the side-effects  in the group of patients who were stepped down compared to those who were not. Was there any improvement in these variables among those who were stepped down (whether fewer new diagnoses or improvement in symptoms [e.g. HgbA1c])?3. This may be beyond the scope of data, but I wonder what proportion of patients had true asthma. As the authors allude to in the discussion , many patients who carry a diagnosis of asthma and are started on inhalers never truly have asthma. What proportion of the patients in the cohort had PFTs or a methacholine challenge confirming a diagnosis of asthma? It is possible, as the authors acknowledge, that many patients did not have asthma—in which case, we would expect that stepping down medications would have no effect. Conversely, perhaps those with true asthma may have had more exacerbations and SABA use after being stepped down. 4. The authors note that, in the 107,908 patients in incident cohort, one-third were on an ICS and add-on, of which 94% were on a LABA. What proportion were on combination ICS-LABA versus two separate inhalers (ICS and LABA)? It would be interesting to examine whether being on a combination product affects the likelihood of being stepped down.5. Of the 107,908 patients who were on an ICS-LABA combination, how many were on ICS-formoterol? The approach of using Symbicort as needed for mild asthma is new in the guidelines. But I wonder whether some clinicians in the UK were already doing this, in which case some of those on an ICS-LABA may not be getting stepped down because they are already on a low intensity therapy (i.e. ICS-formoterol PRN).MinorLine 77: This should be "is obtained with a low-dose" rather than "is obtained with low-dose."Line 110: This should be: "Prescription data were…" rather than "prescription data was..."Line 121: Does excluding non-HES linked patients affect the generalizability? Is there any reason to think that non-HES linked patients are different from HES-linked patients? This may be worth commenting on in the limitations.Line 286: This should be "…a higher number of patients, around one-third, who were prescribed…" rather than "a higher number of patients, around one-third, that were prescribed…"Line 297: This should be "Perhaps this is not a surprising finding…" rather than "Perhaps not a surprising finding…"Line 373: This should be: "…excluding patients who decreased…" rather than "…excluding patients that decreased…"*** Reviewer #3: This is an analysis of the Clinical Practice Research Datalink (UK). The authors used observational data to describe asthma medication patterns with a focus on health outcomes and costs of stepping down asthma medications. The primary conclusion is that higher doses and numbers of asthma medications were prescribed in the UK from 2001-2017, and that most patients can safely reduce them, at a high cost savings.Major comments:1-One of the most interesting questions related to step down that was not considered in this analysis is listed as an asterisk in Table 1 . Why not? I could not find in the methods section where this choice is explained. Stopping all controller meds  is probably the highest risk step down . Also, it is potentially very relevant to new recommendations which suggest all asthma patients should use some level of ICS (intermittent or continuous). Without information on this step down risk, it is difficult to broadly state that step down moves do not adverse affect outcomes. I think the authors either need to analyze this group or be more precise in describing which step down types are likely low risk, and which were not analyzed.2-I think the following variables should be defined more clearly, as in how they were identified within the dataset and what they mean: "asthma management plan, annual asthma review, and inhaler technique check." I also wonder if having seen a specialist is another variable that should be included. 3-The final concluding statement (lines 391-394) which follows "In summary" focuses on not stepping up (which was a descriptive trend finding) and I think most of the analysis is related to outcomes of stepping down. Therefore, the authors may consider a summary statement that includes stepping down.4-How to accomplish stepping down (i.e. how to solve this problem) is not clear from their data. Having annual visits, checking inhaler technique, and an asthma management plan do not seem to be related to step down. Are there any patterns from their data that suggest a solution? Are there signs of stepping down to ICS PRN and that this could be a successful strategy?Other comments:1-Introduction section is concise and clear.2-Sensitvity analyses are appropriate3-Line 154-155--is there validation or a reference to justify 1 or more relievers as cut off?4-Supplementary Figure 2 is very helpful. I suggest the authors consider moving this to the main document.***Any attachments provided with reviews can be seen via the following link:[LINK] 6 Apr 2020AttachmentSteppingDown_ResponseToReviewers_5April2020.docxSubmitted filename: Click here for additional data file. 1 May 2020Dear Dr. Bloom,Thank you very much for re-submitting your manuscript "Health and cost impact of stepping-down asthma medication: a UK population-based observational study, 2001 - 2017" (PMEDICINE-D-20-00031R2) for consideration at PLOS Medicine.I have discussed the paper with editorial colleagues and our academic editor, and it was also seen again by three reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. 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For such statements, authors must provide supporting data or cite public sources that include it.Please ensure that the paper adheres to the PLOS Data Availability Policy .Please make that "data are" at line 137.Please remove the copyright information at line 143 . Please add full access details to reference 26, and any other references that lack it. Please remove the header "Page number" from the rightmost column of your attached STROBE checklist, and the numbers below if these are page numbers . Please restructure this column to provide section details  and paragraph numbers.Comments from Reviewers:*** Reviewer #1: The authors have adequately responded to all points previously raised, in their response. However, it seems that some line numbers referred to in the author response may have shifted ; in particular, the response for Point 4 on "most randomised controlled trials used 50% step-down and a larger step-down would be more likely to identify an effect if there as one" was not readily encountered in the text. Other than these, there are no further concerns on our part.*** Reviewer #3: The authors are responsive to reviewer feedback. Overall, the methods, interpretation, and communication of the findings are excellent. A few additional points to consider:1. The propensity score analysis strengthens the conclusion. I was able to find a description of the methods for the PS, but I did not find the PS in Table S5 as suggested in the authors' responses. I could not find this info listed in a table. I apologize if I missed this. Can the authors please double check to confirm they included this information? 2. I disagree with the authors' decision not to consider the outcomes when patients completely stop ICS, an event that is more likely to result in increased exacerbation than a decrease in controller meds . Seeing this group and showing a negative outcome would increase the validity of using the dataset for outcome assessment. The argument that these patients are judged not to have asthma is an assumption that may hold for a fraction of patients who completely stop controller medications. However, many others likely stop on their own (without provider direction) or revert back to SABA prn approaches, an accepted GL management option for intermittent asthma prior to GINA 2019 GL release. 3. I agree with the choice not to analyze step down to LABA monotherapy, as this is not an accepted or GL recommended asthma therapy.***Any attachments provided with reviews can be seen via the following link:[LINK] 9 Jun 2020Dear Dr Bloom, On behalf of my colleagues and the academic editor, Dr. Aaron Kesselheim, I am delighted to inform you that your manuscript entitled "Health and cost impact of stepping-down asthma medication for UK patients, 2001-2017: population-based observational study" (PMEDICINE-D-20-00031R3) has been accepted for publication in PLOS Medicine. PRODUCTION PROCESSBefore publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. 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Home blood pressure monitoring (HBPM) is recommended for diagnosis, treatment adjustment and management of most hypertension cases in hypertension guidelines from multiple countries. This study aimed to evaluate HBPM behaviour and explore the routine-practice gap in HBPM among Chinese adults with hypertension.Data were collected from 20 communities across three cities and six townships in three provinces  in China between October 2014 and November 2014. In total, 2272 patients with hypertension aged ≥35 years that were registered with a primary health station in their local communities were selected by simple random sampling.P = 0.042; 14.3% vs. 8.1%, P = 0.002; and 19.9% vs. 12.4%, P = 0.005, respectively). Only 16.0% (165/1030) of participants actively reported their HBPM readings to doctors.Among the 2272 participants, 45.3% owned a home blood pressure (BP) monitor. In addition, 27.5% (625/2272) engaged in HBPM weekly or more frequently. Healthcare providers’ advice was the strongest factor contributing to home BP monitor ownership and weekly HBPM behaviour, with odds ratios of 13.50 and 8.97, respectively. Approximately 4.4% of participants had achieved optimal HBPM regimens (duplicate measurements in the morning and evening for 7 days). Patients with uncontrolled office-measured BP were more likely to conduct HBPM regularly in the morning and evening, measure their BP two or three times in each session and maintain 7 consecutive days of HBPM than patients with controlled office BP (8.8% vs. 5.8%, The HBPM strategies specified in hypertension guidelines are seldom achieved in actual practice in China. Only a small proportion of patients actively participate in using HBPM to enhance their hypertension care. HBPM may be improved by healthcare providers offering specific advice and training.The online version contains supplementary material available at 10.1186/s12889-020-09901-0. Previous studies have shown that home blood pressure monitoring (HBPM) is a useful tool to improve long-term adherence to antihypertensive drug treatment among patients with hypertension, and thereby improve hypertension control rates –4. HBPM A HBPM protocol commonly specified in recent hypertension guidelines –10 involCurrently, most healthcare providers encourage patients with hypertension to monitor their own BP at home , 12. Pren = [tα2P (1-P)]/d2, α = 0.05, ta ≈ 2, d = 0.1P. Among patients with hypertension in China, ownership of a home BP monitor ranges from 35 to 65% in different areas. Therefore, a sample size of 750 patients  was considered sufficient for each province. In total, 20 communities were selected: two urban communities and six rural communities from Jiangsu and Shandong province, respectively, and two urban communities and two rural communities from Beijing. Each selected community provided community health records for all patients with hypertension who met the inclusion criteria. Participants were randomly selected from this database using SPSS for Windows version 18.0, based on proportional values. In addition, 15% of the entire sample size was also randomly selected from the community health records for replacement in cases of response failure. In total, 2272 participants were recruited. Written informed consent was obtained from participants, each of whom was required to complete a face-to-face interview using an interviewer-led questionnaire.This cross-sectional survey was conducted in October–November 2014. The study area included three cities  and six townships  located in Shandong Province, Jiangsu Province and Beijing. Patients with hypertension who were registered with primary health stations in their local communities were selected to participate in this study. Inclusion criteria were: 1) aged over 35 years; and 2) a medical history of hypertension for a minimum of 3 months. Exclusion criteria were: 1) patients suffering from serious congestive heart failure, renal insufficiency and requiring dialysis treatment, and patients with cancer; and 2) patients registered in the community health records who did not live in that community. The required sample size was estimated by: A structured questionnaire was developed by a team of researchers at the Beijing Institute of Heart Lung and Blood Vessel Diseases and the Chinese Center for Disease Control and Prevention. The details of the questionnaire are shown in Additional File The questionnaire covered demographic information, family and medical history, lifestyle, antihypertensive medications, Home BP monitor ownership and measurement behaviour, and physical examination. Ownership of a home BP monitor was evaluated with one item: ‘Do you have an upper-arm automatic electronic monitor in your home?’ The item assessing HBPM behaviour comprised four questions: ‘How many days did you conduct HBPM per week?’; ‘What time did you measure your blood pressure each day?’; ‘How many times did you conduct in each measuring session?’; and ‘Did you perform HBPM for 7 consecutive days during the last 3 months?’ Application of HBPM readings was evaluated with two questions that assessed if participants’ doctors requested their HBPM results and whether they proactively reported their HBPM results to their doctors. Participants’ height, weight and BP were measured during a physical exam. Office BP was measured using Omron HBP-7071 with a standard cuff size  on the right arm, supported at the level of the heart. BP was measured with the participant in a sitting position at fixed time from 9:00 to 12:00 in the morning, after taking antihypertensive medicines. The participants rested for at least 5 min in a seated position, and two BP measurements were taken 1–2 min apart and averaged for the record. An additional measurement was taken if the first two readings differed by > 5 mmHg, and the mean value of the three readings was recorded in these cases . The hom2, and obesity was defined as a BMI of ≥28.0 kg/m2.We defined uncontrolled office BP as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg, and controlled office BP as SBP < 140 mmHg and DBP < 90 mmHg. Optimal home BP control was defined as a BP < 135/85 mmHg. Home BP monitor ownership was defined as participants who had an upper-arm automated electronic BP monitor in their home. The prevalence of HBPM was defined as the proportion of participants who measured their BP at home and conducted measurement at least weekly. Regular HBPM behaviour was defined as participants who: 1) conducted HBPM at least weekly; 2) took at least two readings 1–2 min apart in the morning before taking medications and in the evening before supper; and 3) conducted HBPM for 7 consecutive days before a clinic visit. History of ischemic stroke was defined as: a history of symptoms/signs such as numbness, abnormal speech, transient blindness, vertigo, nausea, deviated eyes and mouth, hemiplegia or dribbling; consistent signs on a brain computed tomography or magnetic resonance imaging; and a diagnosis of ischemic stroke by a neurologist . The presence of coronary heart disease (CHD) was defined by a history of coronary artery bypass grafting or coronary stent implantation, or hospitalisation for myocardial infarction. A family history of ischemic CVD was defined as a diagnosis of ischemic stroke or CHD in a first-degree relative (sibling or parent). Current smokers were defined as those who reported having smoked ≥100 cigarettes during their lifetime and were smoking every day or some days at the time of interview. Current alcohol drinkers were defined as drinking alcohol once or more per week during the previous 12 months. For adult males, alcohol drinking was defined as daily drinking over 750 ml of beer, over 250 ml of wine, or over 75 g of 38-degree alcoholic liquor. For adult females, these quantities were 450 ml, 150 ml and 50 g, respectively. Body mass index (BMI) was calculated as body mass in kilograms divided by height in meters squared. An overweight status was defined as a BMI of 24.0–27.9 kg/mP-values were two-tailed, and P-values less than 0.05 were considered statistically significant.Data were input twice to guarantee data accuracy. If the data from the two databases were inconsistent, the original data on the questionnaire were rechecked. Statistical analyses were performed with SPSS for Windows version 18.0 . Chi-square tests were used to compare differences in proportions of different groups. Multiple backward stepwise logistic regression analysis was performed to identify factors influencing home BP monitor ownership and weekly HBPM behaviour. On the basis of chi-square tests, significant variables were entered into a multivariate model. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated for each independent variable. All reported n = 977, female n = 1295) were included in the analyses. Participants’ age ranged from 35 to 93 years, with a mean age of 64.2 ± 10.9 years. In total, 1141 (50.2%) participants were from urban areas and 1131 (49.8%) were from rural areas. Statistically significant differences were identified for all characteristics across the three provinces  except sex. Table In total, 2295 participants were enrolled in this study. After eliminating 23 incomplete questionnaires 2272 participants  participants were treated for hypertension, 991 (46.3%) had controlled office BP and 1541 (67.8%) had received advice on HBPM from a healthcare professional. There were 1030 (45.3%) participants who had a home BP monitor: 77.1% in Beijing, 34.1% in Jiangsu and 23.9% in Shandong. HBPM was performed weekly or more frequently by 27.5% (625/2272) of participants. Table Multivariate regression analysis showed that age, urban versus rural location, education level, other family members with hypertension, history of CVD, antihypertensive medication, office BP control and advice on HBPM from healthcare providers were associated with home BP monitor ownership. All of the above factors were correlated with weekly HBPM behaviour, except history of CVD. Healthcare providers’ advice was the strongest factor contributing to home BP monitor ownership and weekly HBPM behaviour, with ORs of 13.50 and 8.97, respectively (Table n = 1598). Controlled office BP was significantly associated with education level, duration of hypertension, current drinking status and BMI, with ORs of 1.35 , 0.81 (95%CI: 0.68–0.95), 0.66 (95%CI: 0.48–0.88) and 0.61 (95%CI: 0.49–0.76), respectively. No significant relationship was found between office BP control and weekly HBPM, even after adjusting for the other covariates. Additional File We also conducted logistic regression analysis for treated patients with hypertension to show the relationship between controlled office BP and HBPM n = 598. ContP = 0.042). Furthermore, 8.1% of participants with controlled office BP measured their BP two or three times, compared with 14.3% of those with uncontrolled office BP (P = 0.002). Participants with uncontrolled office BP (19.9%) were more likely to conduct HBPM for 7 consecutive days than those with controlled office BP . Overall, participants with controlled office BP had a lower optimal HBPM rate (duplicate measurements in the morning and evening for 7 days) than those with uncontrolled office BP .Table P <  0.001). Only 16.0% (165/1030) of participants proactively reported their HBPM readings to their doctors, and this was statistically significantly higher in those with uncontrolled office BP than those with controlled office BP .We asked participants who performed HBPM if their doctors requested their HBPM results and if they proactively reported their HBPM results to their doctors. Doctors requested HBPM results from 31.8% (328/1030) of participants. Doctors were more likely to request HBPM results from those with uncontrolled office BP than those with controlled office BP  or evening (before bedtime) (n = 57) BP values. The control rate of morning and evening BP was 52.6 and 64.9%, respectively. Optimal morning BP was higher among participants with an office BP < 120/80 mmHg, but the difference was not significant (P = 0.061) , and it was more likely to be higher among those with an office BP < 120/80 mmHg. Only a few participants provided morning (ime) n = 7 BP valuThis study assessed the status of home BP monitor ownership and regular HBPM behaviour among Chinese adults with hypertension. The results showed that nearly half of the participants had a home BP monitor, but this varied across different provinces. More than one-quarter of participants reported weekly HBPM. The HBPM regimens specified in hypertension guidelines are seldom achieved in actual practice. Only a small group of participants actively discussed their HBPM readings with their doctors. Healthcare professionals’ advice was the strongest factor contributing to home BP monitor ownership and weekly HBPM.Use of HBPM has progressively increased over the last two decades. Initially, around 20% of patients with hypertension in developed countries used HBPM , 19, witVarious factors may affect an individual purchasing a home BP monitor and using HBPM. Previous studies among general patients with hypertension (primary care or community settings) have shown inconsistent results. Some studies reported that patients with a higher education level, higher income, male sex and a younger age were more likely to adopt HBPM , 22, 23,Previous studies defined regular HBPM as a respondent’s self-report of monitoring their own BP at home, and performing this at least weekly , 23. AccHBPM use remains low and poor adherence to hypertension guidelines may be attributable to barriers at the patient, clinician, and healthcare system levels : 1) patiClinicians seldom use HBPM instead of office measurements for treatment adjustment. A Canadian study noted that only 19.0% of primary physicians used HBPM readings to guide therapy , althougOptimal BP control at home was obtained among participants with controlled office BP, but optimal morning BP control was significantly lower than other time BP control. Previous studies showed 50–60% of patients with controlled office BP had an elevated morning BP , 33. OurSeveral limitations of this study should be noted. First, given that the sample size was not large, the results may not be representative of all urban and rural areas in Shandong, Jiangsu and Beijing. Second, we did not investigate patients’ knowledge of HBPM and common reasons for not using HBPM, and therefore cannot validate assumptions regarding such reasons. Third, there was no consideration of advice from healthcare providers to investigate their efficacy; even if there was standard plan for HBPM in the guideline, guideline adherence was not evaluated. Fourth, the rate of home BP control was not representative because the results were not based on the uniform measuring standard and were from a small group of patients. In addition, we did not confirm whether participants measured their home BP using appropriate BP monitor  and a proper measurement technique. These details might have led to measurement errors. Reporting bias also existed because home BP monitors did not have a log-memory function.In this study, we found that home BP monitor ownership was relatively low in rural areas and varied across different areas in China. The recommendations for HBPM as specified in hypertension guidelines are seldom achieved in current practice among Chinese adults with hypertension. Patients with uncontrolled hypertension are more likely than those with controlled hypertension to report their home BP readings to their doctors, but only a small proportion actively participate in using home BP measurements to enhance their care. HBPM may achieve greater success through specific advice and training by healthcare providers. New systems are needed to systematically collect home BP data and provide this information routinely to health professionals.Additional file 1. Home BP monitor ownership and measurement of a structured questionnaire developed for this study and independent determinants of controlled office BP among treated hypertensive sample. The survey instrument used in the study to assess home BP monitor and routine-practice of HBPM among Chinese adults with hypertension. Table S1. Home BP monitor ownership and routine practice of HBPM survey. The questions and possible responses used in the assessment of home BP monitor ownership, HBPM weekly and optimal HBP monitoring behavior. Table S2. Health care providers’ HBPM practice survey. The data used to assess the value of health care providers on HBPM and the application of HBPM readings for treatment adjustment. Table S3. Physical examination. The data used in the assessment of overweight or obesity and control of office blood pressure. Table S4. Summary of independent determinants of office BP control. OR and 95% CI indicated the correlation between HBPM weekly or other factors and controlled office BP among treated hypertensive patients.


Increased right ventricular systolic pressure (RVSP), a surrogate marker for pulmonary hypertension, is common in patients with end-stage kidney disease. Limited data suggest improvement of RVSP with intensive dialysis, but it is unknown whether these improvements translate to better clinical outcomes.We conducted a retrospective single center cohort study at the Toronto General Hospital. All patients who performed intensive home hemodialysis (IHHD) for at least a year between 1999 and 2017, and who had a baseline as well as a follow-up echocardiogram more than a year after IHHD, were included. Patients were categorized into two groups based on the RVSP at follow-up: elevated (≥ 35 mmHg) and normal RVSP. Multivariate and cox regression analyses were done to identify risk factors for elevated RVSP at follow-up and reaching the composite endpoint , respectively.One hundred eight patients were included in the study. At baseline, 63% (68/108) of patients had normal RVSP and 37% (40/108) having elevated RVSP. After a follow-up of 4 years, 70% (76/108) patient had normal RVSP while 30% (32/108) had elevated RVSP. 8 (10%) out of the 76 patients with normal RVSP and 15 (47%) out of the 32 patients with elevated RVSP reached the composite endpoint of death, cardiovascular hospitalization or technique failure. In a multivariate analysis, age, diabetes and smoking were not associated with elevated RVSP at follow-up. Elevated RVSP at baseline was not associated with a higher likelihood in reaching the composite endpoint or mortality.Mean RVSP did not increase in patients on IHHD over time, and maintenance of normal RVSP was associated with better clinical outcomes.The online version contains supplementary material available at 10.1186/s12882-020-02159-z. Right ventricular dysfunction and pulmonary hypertension (PH) are common in patients on conventional in-center hemodialysis) and have been reported in up to 50% . A studyThe aim of this study was to investigate the longitudinal effect of intensive hemodialysis on right ventricular systolic pressure (RVSP) as a surrogate marker for PH. Additionally, we investigated possible risk factors for elevated RVSP over time and associated clinical outcomes. We hypothesized that RVSP in patients undergoing intensive HD would not increase at follow-up due to effective extracellular volume control. We ascertained if changes in RVSP correlate with changes in left atrial pressures. Further, we aimed to examine if other factors contributed to the development of elevated RVSP.We performed a retrospective single center cohort study at Toronto General Hospital (TGH). All patients who initiated IHHD between 1 January 1999 and 31 January 2017, and had an echocardiogram at dialysis initiation and a follow-up echocardiogram at least a year after IHHD initiation. Patients on IHHD for less than a year or with missing echocardiographic information at baseline or follow-up were excluded. Patients with tricuspid regurgitation were excluded due to missing RVSP measurement. The study was conducted with adherence to the Declaration of Helsinki and approved by the University Health Network Research Ethics Board.IHHD was defined as ≥16 h of dialysis per week based on the prescribed regimen at the end of home hemodialysis training. A standard prescription consisted of five nights or more for at least 7 hours (35 h per week).Echocardiograms were performed before a hemodialysis session at baseline when initiating IHHD and yearly thereafter. RVSP was measured by estimating the right ventricle–right atrial pressure gradient from the tricuspid regurgitation (TR) maximal velocity. Normal RVSP was defined as < 35 mmHg , 10. NorPatients were categorized into two groups based on RVSP at baseline: normal RVSP (< 35 mmHg) and abnormal RVSP (≥35 mmHg).The primary outcome was the proportion of patients with normal and abnormal RVSP at follow-up, respectively. Secondary outcomes included the composite endpoint of technique failure, cardiovascular events or death and possible risk factors for this composite endpoint. Technique failure was defined as permanently switching to another renal replacement therapy modality such as peritoneal dialysis or in-center hemodialysis. Cardiovascular events consisted of stroke, myocardial infarction, unstable angina, arrhythmia and heart failure.Baseline patient characteristics were collected at the start of IHHD. The following variables were collected: demographic data , body mass index (BMI), cause of end-stage kidney disease (ESKD), type of renal replacement therapy prior to intensive hemodialysis , renal transplantation), initial vascular access type and access type at follow-up , arteriovenous fistula (AVF), arteriovenous graft (AVG)), fistula or graft flow if present, duration of ESKD, RVSP on baseline echocardiogram, co-existing medical conditions , peripheral vascular disease) and blood pressure medications at baseline and after 1 year.Demographic data, time of dialysis initiation and cause of end-stage kidney disease were abstracted form TGH IHHD database. Information on comorbidities, type of renal replacement therapy prior to intensive hemodialysis and initial access type were manually collected from patient’s medical records. Duration of ESKD was defined from initiation of any renal replacement therapy (RRT) until inclusion in into the study. If the exact date of RRT initiation was not available the midpoint of the indicated month or year was used, respectively. CAD was defined as previous myocardial infarction, coronary artery bypass graft or established CAD on imaging. Peripheral vascular disease was defined as vascular calcification on imaging with symptoms of peripheral hypoperfusion.Baseline characteristics and covariates were described using mean and standard deviation or proportions were used. Continuous variables were compared using the Student t or Wilcoxon rank sum test. Chi-square and McNemar test were used to compare proportions. Linear regression analysis was used to investigate correlation of RVSP and left atrial pressure. Multivariate logistic regression analysis was conducted to investigate risk factors for increased RVSP at follow-up. To investigate the impact of different clinical variables on the composite endpoint, a Cox regression model was used. A Kaplan-Meier plot was used to evaluate the time to composite endpoint in patients with normal RVSP and elevated RVSP at follow-up. All analyses were performed using STATA version SE 14.2 .The study cohort is defined in Fig. At baseline, 63% (68/108) of patients had normal RVSP and 37% (40/108) having elevated RVSP.Of the 68 patients with normal RVSP at baseline, 22% (15/68) had elevated RVSP at follow-up  and peripheral vascular disease  were both significantly more prevalent in patients with elevated RVSP at follow-up. All other baseline characteristics including blood pressure therapy at baseline and after 1 year on IHHD did not differ between patients with normal and elevated RVSP at follow-up.At a mean follow-up of 4 years, 70% (76/108) patient had normal RVSP while 30% 32/108) had elevated RVSP (Table /108 had Eight (10%) out of the 76 patients with normal and 15 (47%) out of the 32 with elevated RVSP at follow-up reached the composite endpoint of death, cardiovascular hospitalization or technique failure. Three (4%) and eight (25%) deaths occurred in patients with normal and elevated RVSP at follow-up, respectively. Three (4%) patients with normal and five (16%) patients with elevated RVSP developed technique failure. Hospitalization due to cardiovascular events was observed in two patients (3%) with normal (stroke and arrhythmia) and four (13%) with elevated  RVSP at follow-up. Out of the entire cohort, 25 (23%) patients received a kidney transplant during the study period, 17 (23%) of patients with normal and 8 (24%) with elevated RVSP at follow-up.p = 0.18; Fig. p = 0.01; Fig. In univariate logistic regression analyses, only elevated RVSP at baseline was significantly associated with elevated RVSP at follow-up (OR 2.4 [95% CI 1.0–5.5]). In multivariate analysis, none of the investigated parameters were significantly associated with elevated RVSP at follow-up Table . Kaplan-We also conducted a sensitivity analysis using a cut-off of ≥40 mmHg for elevated RVSP with similar results  in our cohort undergoing IHHD, while new onset or worsening RVSP is a known risk in patients undergoing i in-center hemodialysis –15. In fp = 0.08). However, there was a correlation of change in RVSP and left atrial pressure over time  and pulmonary vascular resistance determine pulmonary arterial pressure. Dialysis specific risk factors for pulmonary hypertension are mostly volume related and include arteriovenous (AV) access with increased venous volume return, left ventricular dysfunction and hypervolemia. While we had data on AV access status and left ventricular ejection fraction, we did not have information on volume status nor diastolic heart failure. Increased left atrial pressure is indicative for post-capillary PH due to left heart dysfunction, systolic and diastolic. Left atrial pressure was not associated with elevated RVSP in our study Table  nor did ime Fig. . SimilarAV access, AV flow and LVEF showed no association with elevated RVSP at follow-up Table . HoweverChallenged with increasing volume, the pulmonary vascular bed is usually able to adapt by decreasing vascular resistance with only little or no increase in pulmonary arterial pressure. Thereby, increased resistance of the pulmonary vascular bed is key in development of PH . SeveralIn conclusion, there are several possible mechanisms of how IHHD may be protective for pulmonary arterial pressure by optimizing volume status, improving left heart geometry and function, decreasing pulmonary vascular resistance and improving sleep apnea.Our study has several strengths. We are the first to report on serial RVSP measurements over a mean follow-up of over 4 years. While single center design can decrease generalizability, patient management is less heterogeneous. Furthermore, by having baseline echocardiograms we were able to analyze RVSP over time. Finally, we could correlate RVSP with a composite endpoint as well as death due to detailed documentation of clinical endpoints such as hospitalization and technique failure. While we acknowledge that there are non-clinical reasons for technique failure such as patient’s choice, it is indicative for frailty in a self-care setting.There are several limitations to our study. Patients suitable for IHHD tend to differ from patients undergoing in-center hemodialysis. A study comparing baseline characteristics from the Frequent Hemodialysis Network (FHN) daily and nocturnal cohorts to the USRDS cohort showed that patient undergoing frequent dialysis tend to be younger, are predominantly male, and differ in the prevalence of underlying kidney disease (more glomerulonephritis and less diabetic nephropathy) . PrevaleUsing only one echocardiogram at follow-up as well as inter-observer variability are possible sources of undetected fluctuations of RVSP. While we tried to correct for multiple co-morbidities and clinical conditions, we cannot exclude residual confounding. Small sample size, limited generalizability and missing control group are additional limitations due to the retrospective single center design. While we used treatment failure as part of the composite endpoint as a marker for frailty, we acknowledge that there are non-clinical reasons for changing treatment such as patient choice. Finally, although measuring RVSP with echocardiograms is non-invasive and economical, the gold standard for measuring PH is by right heart catheterization.In our retrospective study, the number of patients with elevated RVSP did not increase over a mean follow-up of 4 years. Furthermore, the majority of patients with elevated RVSP at baseline had normalization of RVSP at follow-up and IHHD might therefore be an option for patients with ESKD and elevated pulmonary arterial pressure.Additional file 1: Table S1. Characteristics of patients with elevated RVSP defined as a cut-off of ≥40 mmHg and normal RVSP at follow-up.Additional file 2: Table S2. Multivariate analysis for elevated RVSP at follow-up defined as ≥40 mmHg.Additional file 3: Table S3. Cox proportional hazards analysis of the risk of the composite end point of death, technique failure and CV-related hospitalization using cut off of ≥40% for elevated RVSP.Additional file 4: Figure S1. Flow diagram (≥40 mmHg).Additional file 5: Figure S2. Composite endpoint free survival in patients with elevated (≥40 mmHg) and normal RVSP at base line, respectively.


Stroke is one of the leading causes of morbidity and mortality worldwide. Intravenous tissue plasminogen activator and mechanical thrombectomy comprise the two major treatments for acute ischemic stroke. Tissue plasminogen activator has been used for more than two decades and guidelines for hemodynamic management following tissue plasminogen activator administration are well established. However, mechanical thrombectomy is a relatively newer therapy and there is a paucity of evidence regarding hemodynamic management following large vessel occlusion strokes. The important tenets guiding the pathophysiology of large vessel occlusion strokes include understanding of cerebral autoregulation, collateral circulation, and blood pressure variability. In this narrative review, we discuss the current American Heart Association-American Stroke Association guidelines for the early management of acute ischemic stroke during different phases of the illness, encountered at different sections of a hospital including the emergency room, the neuro-interventional suite, and the intensive care unit. There is emerging evidence with regard to post-recanalization blood pressure management following large vessel occlusion strokes. Future research directions will include real-time blood pressure variability assessments, identifying the extent of impaired autoregulation, and providing guidelines related to range and personalized blood pressure trajectories for patients following large vessel occlusion strokes. Stroke is the second leading cause of death affecting six million people every year worldwide . The gloIntravenous tissue plasminogen activator (tPA) was US Food and Drug Administration (FDA) approved for the treatment of acute ischemic stroke in 1996 after the National Institute of Neurological Disorders and Stroke trial and has been the main stay of treatment ever since. After unsuccessful initial attempts involving intra-arterial treatments, the first endovascular clot retriever - Mechanical Embolus Removal in Cerebral Ischemia retriever was FDA-approved in 2004 . After aMT for acute LVO strokes is a relatively new therapy compared to tPA and its peri-procedural guidelines have evolved with emerging evidence. We continue to learn about hemodynamic management following LVO strokes as we gather new data. In the interim, the American heart association/American stroke association (AHA-ASA) guidelines recommend blood pressure goals of lower than 180/105 mmHg following reperfusion, similar to the guidelines following tPA administration . HoweverIn a normal brain, blood vessels constrict in response to high pressures and dilate in response to low pressures, in order to maintain a constant perfusion to the cerebrovascular capillary bed ,21. ThisLVO strokes involve acute occlusion of blood vessels in the anterior circulation, such as the internal carotid, middle cerebral, and anterior cerebral arteries; as well as in the posterior circulation, such as the vertebral, basilar, and posterior cerebral arteries. The occlusion results from thrombosis in an atherosclerotic vessel or from an embolus originating from the heart or cervical blood vessels. After an acute stroke, cerebral autoregulation is known to be impaired, increasing the dependence of cerebral perfusion on the systemic pressures . TherefoDuring ischemic stroke, although the core of the infarct undergoes irreversible damage, the penumbra in the periphery of the infarct can be salvaged . The penBlood pressure variability in the setting of an acute ischemic stroke is due to a complex interplay between autonomic regulation and arterial wall mechanical properties . Over 60A study evaluating the natural history of blood pressure following MT in 68 patients with LVO strokes was reported in 2016 . It was Due to the distinct pathophysiology underlying the problem, it will be most appropriate to discuss the current guidelines in terms of the three phases following an acute ischemic stroke: (a) pre-recanalization phase or initial assessment phase encountered in the emergency department, (b) recanalization phase or procedure phase, when the patient is in the angiography suite for an interventional neuro-vascular approach to treat the thrombus, and (c) early post-recanalization phase, the first 24 hours following thrombectomy, when the patient is managed in the ICU after the procedure .Hypotension and hypovolemia should be prevented to maintain systemic perfusion and support end-organ function . A drop The 2019 AHA/ASA guidelines for the early management of acute ischemic stroke introduced a few new recommendations regarding blood pressure management. The recommendations discussed in this section are class I recommendations unless stated otherwise. The Society of Neuroscience in Anesthesiology and Critical Care recommends that the SBP be maintained between 140 and 180 mmHg during MT . Abrupt In the absence of a randomized controlled trial data for post-recanalization BP management following MT, AHA-ASA guidelines propose a class II recommendation to keep SBP ≤180/105 mmHg during the procedure and in the first 24 hours following the procedure. For completely recanalized patients, the SBP could be kept <180/105 mmHg (class II b) . In spitAHA/ASA guidelines-based SBP goal is arbitrarily set higher in patients with incomplete reperfusion to ensure perfusion to the penumbra through collaterals. However, we now see emerging evidence for post-recanalization BP management that may require incorporation into the subsequent AHA/ASA guidelines.An initial retrospective study in 2017 reported that higher blood pressures may relate to worse outcomes and a 10 mmHg increase in maximum SBP within the first 24 hours after MT was an independent predictor of both worse functional independence and increased mortality at 3 months . This stAs per AHA/ASA guidelines, blood pressure should be measured every 15 minutes in the first 2 hours following tPA or MT, every 30 minutes until the first 6 hours, and only hourly thereafter . AHA/ASAOn the other hand, we acknowledge that lower blood pressure levels can also be harmful. There are ongoing trials to examine the effect of induced hypertension using peripherally acting vasopressors like phenylephrine to ensure better perfusion to the penumbra. There is no conclusive data in favor of such treatment (class IIb), meaning it is possible to improve low blood pressure levels with vasopressors; however, the effects of pressor-based normalized blood pressure on clinical outcomes are not known at this point .The current AHA/ASA guidelines recommend a blood pressure <185/110 mmHg before fibrinolytic treatment and that blood pressure be maintained at ≤180/105 mmHg in the first 24 hours thereafter, if the patient received tPA and/or MT. However, in the light of BEST trial and reflecting on the parameters used in the DAWN trial, we propose the following Blood Pressure goals.(a) For patients who are not recanalized (TICI 0), blood pressure limits of ≤180/105 mmHg should be permitted if these patients received tPA. One can be more liberal regarding blood pressure if these patients did not receive tPA and attempt to reduce the blood pressure by 15% of the baseline only if the presenting blood pressure is greater than 220/110 mmHg. In patients who did not receive tPA and could not be recanalized, induced hypertension is a consideration.(b) For patients who are partially recanalized , the blood pressure goal should be ≤160/90 mmHg. Higher SBP up to 180 mmHg may be permitted in cases of neurological deterioration. It is noteworthy that higher blood pressure variability and disruption of autoregulation may persist longer in these patients ,68. Acut(c) For patients who are completely recanalized , blood pressure goals should be ≤160/90 mmHg. Greater blood pressure variability may be a predictor of poor outcomes in these patients. Therefore, acute peak and fall in blood pressure should be avoided in this group.(d) More intensive blood pressure goals (<140 mmHg) may be required for patients who are fully recanalized but have symptomatic intracerebral hemorrhage (ICH) or ICH on imaging.A significant but slow drop in blood pressure is seen in the early post-recanalization phase and more in successfully recanalized patients as compared to non-recanalized patients. Thereafter, a plateau in blood pressure is achieved after 10-12 hours of recanalization. The physiological mechanism behind this phenomenon is unclear ,71. TherHemodynamic management of LVO stroke patients require close blood pressure monitoring and its careful management for at least the first 24 hours after MT. Emerging research utilizing continuous and noninvasive methods to identify cerebral autoregulatory ranges and the use of multimodal monitoring to assess real-time blood pressure variability, may guide the personalized management of blood pressure. In this narrative review, we aimed to summarize the blood pressure management guidelines for the care of LVO stroke patients with specific emphasis on blood pressure variability.