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• Reply to: ‘Comment on: Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis by Edwards et al.’ by Wewege et al.
  Jamie J Edwards, Jonathan D Wiles and Jamie M O'Driscoll
  Published on: 16 May 2022
• Comment on: ‘Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis’ by Edwards et al.
  Michael A Wewege, Harrison J Hansford and Matthew D Jones
  Published on: 13 April 2022

• Published on: 16 May 2022

  Reply to: ‘Comment on: Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis by Edwards et al.’ by Wewege et al.

  • Jamie J Edwards, PhD Researcher Canterbury Christ Church University
  • Other Contributors:
    • Jonathan D Wiles, Principal Lecturer
    • Jamie M O'Driscoll, Reader in Cardiovascular Physiology

  Reply to: ‘Comment on: Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis by Edwards et al.’ by Wewege et al.

  Edwards, J.J., Wiles, J.D., & O’Driscoll, J.M.

  School of Psychology and Life Sciences, Canterbury Christ Church University, Kent, CT1 1QU

  Correspondence to Dr Jamie O’Driscoll, School of Psychology and Life Sciences, Canterbury Christ Church University, North Holmes Road, Canterbury, Kent, CT1 1 QU. Email: jamie.odriscoll@canterbury.ac.uk; Telephone: 01227922711.

  We thank Wewege et al. (1) for their assessment and comments on our recent work (2), highlighting their concerns over the employed statistical analysis approach, which they suggest may “invalidate the results”.

  We take these comments seriously and have therefore re-performed the analysis as suggested by Wewege et al. (1) and individually addressed the points raised within this rapid response.

  Wegewe et al. (1) state that the marked differences found in our study “contrast previous findings”, with reference to a previous large-scale network meta-analysis by Naci et al. (3). As detailed, Naci et al. (3) did not include high intensity interval training (HIIT), and the lower blood pressure (BP) changes observed can be attributed to a combination of differences to the present study, including a smaller pool of lower quality iso...

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  Reply to: ‘Comment on: Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis by Edwards et al.’ by Wewege et al.

  Edwards, J.J., Wiles, J.D., & O’Driscoll, J.M.

  School of Psychology and Life Sciences, Canterbury Christ Church University, Kent, CT1 1QU

  Correspondence to Dr Jamie O’Driscoll, School of Psychology and Life Sciences, Canterbury Christ Church University, North Holmes Road, Canterbury, Kent, CT1 1 QU. Email: jamie.odriscoll@canterbury.ac.uk; Telephone: 01227922711.

  We thank Wewege et al. (1) for their assessment and comments on our recent work (2), highlighting their concerns over the employed statistical analysis approach, which they suggest may “invalidate the results”.

  We take these comments seriously and have therefore re-performed the analysis as suggested by Wewege et al. (1) and individually addressed the points raised within this rapid response.

  Wegewe et al. (1) state that the marked differences found in our study “contrast previous findings”, with reference to a previous large-scale network meta-analysis by Naci et al. (3). As detailed, Naci et al. (3) did not include high intensity interval training (HIIT), and the lower blood pressure (BP) changes observed can be attributed to a combination of differences to the present study, including a smaller pool of lower quality isometric exercise training (IET) trials. Specifically, our analysis includes 8 trials that would not have been published at the time Naci et al. (3) performed their systematic search and we contrarily ensured the omission of older trials that did not meet today’s standards of methodological rigour. We would also strongly recommend a full exploration of the supplementary file of Naci et al. (3) (appendix 8) which clearly supports the comparative efficacy of IET.

  The next concern raised by Wegewe et al. states that: “None of the included trials in this review appear to contain both isometric and HIIT interventions; therefore, the authors are unable to ‘directly compare’ the interventions”. As the authors (1) are probably aware, there is currently no direct randomised control trial data on the effects of IET versus HIIT. Consequently, the only available statistical approach to meta-analysing the current data is via indirect means, as performed in the present study. We agree that our wording within the first paragraph of the discussion, where we refer to “directly comparing” these modes, should not be interpreted in an analytical context but rather this statement was made in consideration of the relevant limitations of the wider literature. In hindsight, we agree that this could have been overtly explained for those not fully conversant with the current literature.

  The primary concern raised by Wegewe et al. (1) questions whether the chosen statistical approach is “correct”, citing the potential of being misleading and prone to bias. We agree that there are limitations of this method of analysis; however, to label the employed statistical approach as “incorrect” is far too simplistic and implies that the process of this type of analysis selection can only be viewed in terms of black-and-white. There are advantages and limitations to all employed statistical analyses and the decision for employing the current method was informed based on the available data. As stated by Wegewe et al. (1), many of the HIIT studies (6 to be exact) did not utilise a non-intervention control group, but instead included a moderate-intensity training group. Thus, to follow the statistical method advised by Wegewe et al. (1) would mean the omission of 6 effects sizes from the final HIIT analysis, which would carry its own bias implications. However, to remove any doubt regarding the validity of our published findings, we have performed the alternative method of analysis as recommended by Wegewe et al. (1), following a between-group random-effects (exercise versus non-intervention control only) analysis. The results are as follows:

  Results from the current approach

  IET - sBP: -8.50 (95% CI: 6.49-10.52, p<0.001) dBP: -4.07 (95% CI: 3.04-5.10, p<0.001)
  HIIT - sBP: -2.86 (95% CI: 1.11-4.62, p=0.001) dBP: -2.48 (95% CI: 1.49-3.48, p<0.001)

  Results from the alternative approach suggested by Wegewe et al

  IET - sBP: -8.04 (95% CI: 6.37-9.72, p<0.001) dBP: -3.23 (95% CI: 1.91-4.55, p<0.001)
  HIIT - sBP: -3.33 (95% CI: 1.17-5.48, p=0.003) dBP: -2.15 (95% CI: 0.53-3.78, p=0.009)

  As such, following the statistical technique proposed by Wegewe et al. (1), IET still produces statistically and clinically significant reductions in BP compared to HIIT. Importantly, regardless of whether our original, or their proposed statistical approach is employed, the primary results do not meaningfully change. Thus, any concern presented by Wegewe et al. (1) regarding changes in exercise guideline recommendations for the incorporation of IET for the management of BP can now be removed.

  References

  1 Wewege MA, Hansford HJ, Jones MD. Comment on: ‘Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis’ by Edwards et al. Br J Sports Med Published Online First: 2022. https://bjsm.bmj.com/content/56/9/506.responses#comment-on-‘isometric-exercise-versus-high-intensity-interval-training-for-the-management-of-blood-pressure-a-systematic-review-and-meta-analysis’-by-edwards-et-al
  2 Edwards J, Caux A De, Donaldson J, et al. Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis. Br J Sports Med 2021;:bjsports-2021-104642. doi:10.1136/BJSPORTS-2021-104642
  3 Naci H, Salcher-Konrad M, Dias S, et al. How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. Br. J. Sports Med. 2019;53:859–69. doi:10.1136/bjsports-2018-099921

  Conflicts of Interest

  We are the authors of the published work.

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  Conflict of Interest:
  We are the authors of the published work.

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• Published on: 13 April 2022

  Comment on: ‘Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis’ by Edwards et al.

  • Michael A Wewege, PhD Candidate University of New South Wales; Neuroscience Research Australia
  • Other Contributors:
    • Harrison J Hansford, PhD Candidate
    • Matthew D Jones, Lecturer

  In their systematic review and meta-analysis, Edwards et al. (1) aimed to ‘directly compare’ the efficacy of isometric exercise and high-intensity interval training (HIIT) for the management of resting blood pressure. They included 38 randomised controlled trials (18 for isometric, 20 for HIIT) in their pairwise meta-analysis and concluded that isometric exercise appears to be superior to HIIT for improving both systolic blood pressure (mean difference between exercise types = 5.29 mmHg, 95% confidence interval 3.97 to 6.61) and diastolic blood pressure (mean difference between exercise types = 3.25 mmHg, 95% confidence interval 2.53 to 3.96). We were interested in these marked differences because they contrast previous findings (2) and, if correct, may necessitate important changes to guidelines. However, in further examining the article, we identified some issues that we believe require attention as they may invalidate the results and are relevant to readers of this journal.

  None of the included trials in this review appear to contain both isometric and HIIT interventions; therefore, the authors are unable to ‘directly compare’ the interventions. Instead, by analysing the differences between isometric and HIIT subgroups in the meta-analysis, Edwards et al. (1) are making an inference based on the indirect effect, which assumes that the differences between exercise types can be inferred via a common comparator (in this case, the control group) (3). This is, in effe...

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  In their systematic review and meta-analysis, Edwards et al. (1) aimed to ‘directly compare’ the efficacy of isometric exercise and high-intensity interval training (HIIT) for the management of resting blood pressure. They included 38 randomised controlled trials (18 for isometric, 20 for HIIT) in their pairwise meta-analysis and concluded that isometric exercise appears to be superior to HIIT for improving both systolic blood pressure (mean difference between exercise types = 5.29 mmHg, 95% confidence interval 3.97 to 6.61) and diastolic blood pressure (mean difference between exercise types = 3.25 mmHg, 95% confidence interval 2.53 to 3.96). We were interested in these marked differences because they contrast previous findings (2) and, if correct, may necessitate important changes to guidelines. However, in further examining the article, we identified some issues that we believe require attention as they may invalidate the results and are relevant to readers of this journal.

  None of the included trials in this review appear to contain both isometric and HIIT interventions; therefore, the authors are unable to ‘directly compare’ the interventions. Instead, by analysing the differences between isometric and HIIT subgroups in the meta-analysis, Edwards et al. (1) are making an inference based on the indirect effect, which assumes that the differences between exercise types can be inferred via a common comparator (in this case, the control group) (3). This is, in effect, the simplest version of a network meta-analysis. However, Edwards et al. (1) only analyse the intervention group’s change from baseline from each study (as shown in Figures 2 & 3 of their article) and report separate meta-analyses of the control change from baseline. This method is not correct. Analysing a single group’s change from baseline in a trial, or a meta-analysis, as opposed to the between-group effect (the change/endpoint in the intervention group minus the change/endpoint in the control group), is misleading because several statistical phenomena like regression to the mean and natural history are not accounted for (4, 5). Regression to the mean in hypertension has been shown to be, at times, as large as the effect of treatment itself (6). In using change from baseline values without comparison to control, the data presented in the meta-analyses are now equivalent to cohort studies and causal inferences are unable to be made (7). By extension, attempting to estimate the indirect effect using change from baseline scores, rather than between-group differences, is prone to bias and is not recommended (3).

  We believe that the results and conclusions presented by Edwards et al. (1) may be biased due to the use of change scores, rather than between-group differences, for their comparison between isometric exercise and HIIT. Therefore, we urge caution for anyone who may consider altering their clinical practice until the results are updated.

  Correctly re-estimating the indirect effect of isometric exercise versus HIIT via the control group may provide valuable information to clinicians; the network meta-analysis by Naci et al. (2) found similar effects for endurance exercise and isometric exercise, but did not further explore the potential unique effects of HIIT. However, transitivity – the assumption that it is appropriate to learn about isometric exercise versus HIIT via a common control group – requires strong consideration to ensure the validity of the indirect effect (8). It requires that effect modifiers be similarly distributed across the different comparisons. If intervention duration is thought to modify the effect of exercise, it is important to confirm both studies of isometric exercise versus control (8.2 weeks) and studies of HIIT versus control (8.1 weeks) are delivered for a similar duration in the included studies, which appears to be true. Another effect modifier might be the control group intervention/effect, which does not appear to be similarly distributed across the two comparisons. All isometric exercise studies appear to use a minimal/no exercise control, but several HIIT studies use a moderate-intensity continuous training comparator. Given a no exercise control will have a different effect to a moderate-intensity continuous training control, and these are not similarly distributed across the two exercise types, this will threaten the assumption of transitivity and introduce bias in the indirect effect (8). Therefore, to ensure transitivity holds, it may only be appropriate to include HIIT studies that use a no exercise control. Several other clinical and methodological characteristics may also need to be considered, adding to the complexity of indirect effect estimation, especially as the network of interventions increases. This is best done a priori with a study protocol, utilising a team that contains clinical and methodological/statistical expertise.

  References
  1. Edwards J, De Caux A, Donaldson J, Wiles J, O'Driscoll J. Isometric exercise versus high-intensity interval training for the management of blood pressure: a systematic review and meta-analysis. British Journal of Sports Medicine. 2021:bjsports-2021-104642.
  2. Naci H, Salcher-Konrad M, Dias S, Blum MR, Sahoo SA, Nunan D, et al. How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. British Journal of Sports Medicine. 2019;53(14):859.
  3. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. Journal of clinical epidemiology. 1997;50(6):683-91.
  4. Bland JM, Altman DG. Comparisons against baseline within randomised groups are often used and can be highly misleading. Trials. 2011;12(1):264.
  5. Bland JM, Altman DG. Comparisons within randomised groups can be very misleading. BMJ. 2011;342:d561.
  6. Salam A, Atkins E, Sundström J, Hirakawa Y, Ettehad D, Emdin C, et al. Effects of blood pressure lowering on cardiovascular events, in the context of regression to the mean: a systematic review of randomized trials. J Hypertens. 2019;37(1):16-23.
  7. Tennant PWG, Arnold KF, Ellison GTH, Gilthorpe MS. Analyses of ‘change scores’ do not estimate causal effects in observational data. International Journal of Epidemiology. 2021:dyab050.
  8. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research synthesis methods. 2012;3(2):80-97.

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  Conflict of Interest:
  We have published systematic reviews evaluating exercise for blood pressure management. Michael Wewege was supported by a Postgraduate Scholarship from the National Health and Medical Research Council of Australia, a School of Medical Sciences Top-Up Scholarship from the University of New South Wales, and a PhD Top-Up Scholarship from Neuroscience Research Australia.

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