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Time to benefit for stroke reduction after blood pressure treatment in older adults: A meta‐analysis

Abstract Background Hypertension treatment in older adults can decrease mortality, cardiovascular events, including heart failure, cognitive impairment, and stroke risk, but may also lead to harms such as syncope and falls. Guidelines recommend targeting preventive interventions with immediate harms and delayed benefits to patients whose life expectancy exceeds the intervention's time to benefit (TTB). Our objective was to estimate a meta‐analyzed TTB for stroke prevention after initiation of more intensive hypertension treatment in adults aged ≥65 years. Methods Studies were identified from two Cochrane systematic reviews and a search of MEDLINE and Google Scholar for subsequent publications until August 31, 2021. We abstracted data from randomized controlled trials comparing standard (untreated, placebo, or less intensive treatment) to more intensive treatment groups in older adults (mean age ≥ 65 years). We fit Weibull survival curves and used a random‐effects model to estimate the pooled annual absolute risk reduction (ARR) between control and intervention groups. We applied Markov chain Monte Carlo methods to determine the time to ARR thresholds (0.002, 0.005, and 0.01) for a first stroke. Results Nine trials (n = 38,779) were identified. The mean age ranged from 66 to 84 years and study follow‐up times ranged from 2.0 to 5.8 years. We determined that 1.7 (95%CI: 1.0–2.9) years were required to prevent 1 stroke for 200 persons (ARR = 0.005) receiving more intensive hypertensive treatment. Heterogeneity was found across studies, with those focusing on tighter systolic blood pressure control (SBP < 150 mmHg) showing longer TTB. For example, in the SPRINT study (baseline SBP = 140 mmHg, achieved SBP = 121 mmHg), the TTB to avoid 1 stroke for 200 patients treated was 5.9 years (95%CI: 2.2–13.0). Conclusions More intensive hypertension treatment in 200 older adults prevents 1 stroke after 1.7 years. Given the heterogeneity across studies, the TTB estimates from individual studies may be more relevant for clinical decision‐making than our summary estimate.


Rationale
3 Describe the rationale for the review in the context of existing knowledge.
Page 5 of manuscript Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses.
Page 6 of manuscript

METHODS
Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.
Page 6-7 of manuscript Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.
Page 6 of manuscript (more details provided in the individual systematic reviews) Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.
Page 6 and 7 of manuscript (more details provided in the individual systematic reviews) Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
Page 7 of manuscript (one reviewer) Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Risk of bias was already assessed in the systematic reviews included in this study Effect measures 12 Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results.
Page 7 and 8 of manuscript (TTB analysis)

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
Page 7 of manuscript and Table 1 with list of excluded studies 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Page 8 and 9 of manuscript (DigitizeIt, Stata module) 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
Page 8 of manuscript (Stata module) 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Page 8 of manuscript (Stata module) 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression).
Page 8 of manuscript (I 2 value) 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

N/A
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

N/A
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Page 8 and 9 of manuscript; Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Figure 1; Table 1 Section and Topic Item # Checklist item Location where item is reported Study characteristics 17 Cite each included study and present its characteristics.
Page 9 of manuscript; Table 2 Risk of bias in studies 18 Present assessments of risk of bias for each included study.

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. Figure 3; Supplementary  Table S1 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.  Table S1 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.
Page 10 of manuscript; Figure 3; Supplementary Table S1 20c Present results of all investigations of possible causes of heterogeneity among study results.
Page 10 and 11 of manuscript; Table 2; Figure 3; Supplementary Table S1 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. is the time to prevent one stroke per 100 older persons treated.