Screening for hypertension in adults: protocol for evidence reviews to inform a Canadian Task Force on Preventive Health Care guideline update

Blood pressure is a measure of the force of blood pushing against arterial walls. High blood pressure, or hypertension, is a common condition in which the blood vessels sustain persistently raised pressure [1, 2]. Large-scale population-based studies have found that the relationship between blood pressure and risk of cardiovascular disease is continuous and follows a decreasing gradient with no apparent threshold, at least down to a blood pressure of 115/75 mm Hg [3, 4]. Hypertension is often first observed through office-based screening and then diagnosed with follow-up blood pressure measurements. In Canada, the 2020 Hypertension Canada guideline recommends a threshold of systolic blood pressure (SBP) equal to or greater than 135 mm Hg and/or diastolic blood pressure (DBP) equal to or greater than 85 mm Hg for automated office blood pressure measurement (OBPM) with at least three readings take during the same visit, discarding the first reading and averaging the latter two (or >  = 140/90 mm Hg for manual office blood pressure measurement) for the diagnosis of hypertension [5]. If a patient meets these blood pressure thresholds with OBPM, then ambulatory (ABPM) or home (HBPM) blood pressure measurements are recommended to rule out white coat hypertension (individuals who are hypertensive when measured in office but normotensive in other settings [6]), with thresholds of 135/85 mm Hg used for diagnosis (or >  = 130/80 for 24-h mean for ABPM). Their guidelines differ for individuals with diabetes, where a threshold of manual OBPM >  = 130/80 for 3 or more measurements on different days is recommended for hypertension diagnosis [5].

European and UK standards for the diagnosis of hypertension are similar, with an office-based measurement threshold of > 140/90 followed by confirmatory measurements [7, 8]. In the USA, the American College of Cardiology (ACC) and American Heart Association (AHA) 2017 define hypertension thresholds by stage (stage 1: SBP 130–139 mm Hg and/or DBP 80–89 mm Hg; stage 2: ≥ 140 mm Hg and/or ≥ 90 mm Hg) measured by at least two high-quality measurements obtained on two or more separate occasions [9].

Hypertension is ranked as the leading risk factor for cardiovascular morbidity and death globally [10, 11]. Hypertension is also recognized as the number one contributor to disability-adjusted life years, a measure of overall disease burden defined as the number of years lost due to poor health, disability, or death [10] and is the most common reason for primary care visits in developed countries [12]. The global age-standardized prevalence of hypertension in adults in 2010 (defined as a blood pressure greater than or equal to 140/90 mm Hg) was 31.1% in high-income countries and 31.5% in low- and middle-income countries [11, 13]. A review of population-based Canadian surveys found that while the prevalence of hypertension had remained stable between 1992 and 2009, the rates of controlled hypertension (participants with previously diagnosed hypertension with a blood pressure of < 140/90 mm Hg) had increased, reflecting increases in awareness and treatment [14]. This trend may be shifting, as more recent Canadian data from 2007 to 2017 showed deterioration in hypertension awareness, treatment, and control, especially for older women [15, 16]. Additionally, deterioration in blood pressure control may have been further exacerbated by the COVID-19 pandemic [17]. A recent UK report estimated that almost half a million individuals missed out on treatment of high blood pressure due to COVID-19 [18]. The 2016–2019 Canadian Health Measures Survey revealed a hypertension prevalence of 22.6% (defined as an average blood pressure measurement of >  = 140/90 mm Hg over five readings or self-reported use of antihypertensive medications) in Canadians aged 20–79 years and an increase from 19.6% of adults reported in 2007–2009 [19]. However, this is not age adjusted and may be reflective of the aging Canadian population.

Healthcare organizations and professionals have made substantial efforts to reduce the burden of hypertension by increasing hypertension awareness, treatment, and control [20]. One study found that 84% of Canadians aged 20 to 79 with hypertension were aware of their condition between 2012 and 2015. However, young Canadians aged 20 to 39 were much less likely to be aware of being hypertensive (65%) than older individuals [21].

Blood pressure is regulated by a complex system of neurohumoral factors; an imbalance in any of these factors could contribute to the development of hypertension [22]. Hypertension that is caused by other conditions, such as primary hyperaldosteronism, renal disease, or obstructive sleep apnea, is referred to as secondary hypertension [23]. Most patients (90–95%) have primary or “essential” hypertension, in which no cause has been identified [22, 23]. The pathophysiological mechanisms of primary hypertension are thought to be multifactorial, involving both lifestyle and genomic factors [22, 24]. Non-modifiable risk factors include increasing age [25, 26], family history of hypertension [25, 27], and other comorbidities, such as type 2 diabetes mellitus or chronic kidney disease [5]. Modifiable lifestyle risk factors associated with increased risk of hypertension include excessive salt intake [28‐30], low intake of fruits and vegetables [31‐34], physical inactivity [32, 35, 36], alcohol consumption [32, 37, 38], tobacco smoking [27, 39], and being overweight or obese [25, 27, 32, 40, 41]. In North America, the prevalence of hypertension is higher in Black individuals compared with white individuals, as well as in individuals with South Asian or Indigenous ancestry [42]. These differences in risk may be largely explained by dietary patterns, smoking, and social factors such as socioeconomic status [42‐45] in addition to other contributors [46, 47].

Cardiovascular consequences include increased risk of angina, myocardial infarction, congestive heart failure, peripheral arterial disease, and stroke [3]. Beyond cardiovascular disease, hypertension is also a major risk factor for chronic kidney disease [48, 49], dementia [50, 51], retinopathy [52], and encephalopathy [53]. Hypertension is a leading modifiable risk factor for cardiovascular morbidity and mortality and all-cause mortality globally, and in Canada [54, 55], high blood pressure is estimated to contribute to more than 10% of the population-attributable fraction of premature deaths worldwide [56]. Globally, high blood pressure is associated with 15.2% of all deaths and 7.4% of all premature death or disability, and there have been numerous calls to action to diagnose and control hypertension to prevent negative health effects [15, 57‐60]. A systematic review evaluated the risk of cardiovascular events and found those with high normal blood pressure (130–139 and 85–89 mm Hg) had an increased risk of cardiovascular events (risk difference 0.69, 95% CI 0.43 to 0.97 per 1000 person years) compared to individuals with low normal or low blood pressure [61]. Associations were also seen for those with grade 1 hypertension (1.81, 95% CI 1.34 to 2.34 per 1000 person years) and grade 2 hypertension (4.24, 95% CI 2.58 to 6.48 per 1000 person years).

Screening aims to detect high blood pressure in people who are asymptomatic and who do not have a previous diagnosis of hypertension. As hypertension rarely has early symptoms prior to an adverse outcome, it is most often not identified without screening [62]. In a 2017 survey of Canadian family physicians, the majority of physicians reported that manual OBPM with a mercury or aneroid device and stethoscope was their most frequent method to screen patients for hypertension, with automated OBPM being the second most popular screening method [63]. OBPM is subject to sources of error, including the white coat phenomenon [6, 64] and errors in the measurement procedure by the blood pressure taker [65‐67]. Blood pressure measurement through ABPM and HBPM methods is therefore recognized as superior to OBPM in accuracy [68] and more strongly associated with cardiovascular morbidity and mortality [69‐71]. However, there is emerging evidence that unattended (no medical personnel in the room) and fully automated OBPM assessment is comparable to awake ambulatory BP readings and may therefore minimize the “white coat” effect [68]. The American College of Cardiology (ACC) and American Heart Association (AHA) 2017 guidelines recommend OBPM both as a screening method for hypertension and to confirm the diagnosis [9]. Standard screening includes routine blood pressure measurements at appropriate clinic visits, regardless of previous measures or the interval since the last measure. Although this approach is simple, it has been suggested that a more nuanced strategy around screening intervals, such as risk-based screening intervals, may be more efficient for the prevention of cardiovascular disease [72‐74]. Practitioners would benefit from clearly defined optimal screening methods, frequency, and target population.

Given the risk of cardiovascular disease, hypertension screening could provide a benefit if previously unrecognized hypertension is diagnosed and brought under control. Evidence supports the efficacy of treating hypertension, both through pharmacological therapies [75‐78] and lifestyle interventions [29, 79‐81]. However, screening programs for hypertension can harm persons, for example, through labeling, overdiagnosis, or overtreatment [82‐84]. Hypertension requires lifelong management, and potential harms, such as psychological effects, adverse effects from medications, and increased burden on both the individual themselves and the healthcare system, must be weighed against the benefits of screening.

In 2012, the Canadian Task Force on Preventive Health Care (“Task Force”) published recommendations on screening for hypertension in adults. Based on moderate-quality evidence from their systematic review, the Task Force recommended the following: (1) blood pressure measurement at all appropriate primary care visits (“appropriate” visits may include periodic health visits, urgent office visits for neurologic or cardiovascular-related issues, medication renewal visits, and other visits where the primary care practitioner deems it appropriate), (2) that blood pressure be measured according to the current techniques described in the 2012 Canadian Hypertension Education Program (CHEP) recommendations for office and out-of-office blood pressure measurement (see Additional file 1) [85], and (3) for people with elevated blood pressure measurement during screening, the 2012 CHEP criteria for assessment and diagnosis of hypertension should be applied to determine whether patients meet diagnostic criteria for hypertension [86, 87]. In 2015, the US Preventive Services Task Force (USPSTF) recommended screening for high blood pressure in adults aged 18 years or older and obtaining measurements outside of the clinical setting for diagnostic confirmation before starting treatment [88]. Regarding screening intervals, the USPSTF recommended annual screening for adults aged 40 years or older and those at increased risk for high blood pressure (i.e., high-normal blood pressure [130 to 139/85 to 89 mm Hg], overweight or obese, and African American). They suggest adults aged 18 to 39 years with normal blood pressure (i.e., < 130/85 mm Hg) and without risk factors be rescreened every 3 to 5 years. The USPSTF released an updated evidence review [89] and hypertension screening recommendations in April 2021 and reaffirmed their 2015 recommendations [90]. Hypertension Canada released guidelines for prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children in 2020. They recommended that healthcare professionals trained to measure blood pressure should assess blood pressure in adults at all appropriate visits to determine cardiovascular risk and monitor antihypertensive treatment [5]. Regarding antihypertensive treatment initiation, Hypertension Canada promotes a risk-based approach to treatment thresholds, with low-risk patient populations (no target organ damage or CVD risk factors) having a threshold of SBP >  = 160 mm Hg and/or DBP >  = 100 mm Hg. The treatment initiation BP threshold is lower (SBP ≥ 130) for those at high risk of CVD (e.g., chronic kidney disease, Framingham risk score >  = 15%, age >  = 75 years) or those with diabetes mellitus (SBP ≥ 130 and/or DBP ≥ 80) [5].

The Task Force is updating their 2012 guideline on hypertension screening in adults because new recommendations and relevant systematic reviews have been published since the original Task Force guideline. Further, the Task Force methods have evolved since 2012 and now consider evidence on patient values and preferences for screening and of screening methods. The hypertension working group will use the evidence from the planned systematic reviews to develop updated recommendations for primary care providers on hypertension screening. The key questions to be addressed are available in Table 1. Figure 1 presents the analytic framework of the KQs, relevant population, interventions, and outcomes to be considered.

This protocol was developed by the Evidence Review and Synthesis Centre (ERSC) at the University of Ottawa (A. B. 1, A. B.2, N. S., B. S., D. M., M. B., J. L., J. F., J. K., F.L., K.P.) in consultation with the hypertension working group consisting of Task Force members (B. J. W., R. G., N. P., G. T. 1, B. D.T.), and with support from working group external clinical experts (C. E. C., J. K., P. L.), and the Science Team (C. G., M. S., G. T. 2). The full Task Force has approved this final version of the protocol, and peer reviewers and stakeholders have reviewed it. The methodology planned for the systematic reviews will follow the Task Force methods manual [91] with additional guidance from the Cochrane Handbook [92] and GRADE handbook [93].

Reporting of this protocol was completed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) checklist [94] (see Additional file 2). The protocol will be registered on PROSPERO. In addition, the protocol will be available on the Open Science Framework (osf.io/8w4tz). The working group, external clinical experts, and Science Team will not be involved in selecting studies, data extraction, or data analysis but may be consulted for advice if required. The ERSC will make all final decisions, and any amendments to the reviews and this protocol will be provided in the final manuscript.

Following development of an extensive scoping and refinement exercise led by the Science Team, the hypertension working group established and finalized the key questions and related PICOTS (population, interventions, comparators, outcomes, timing, and setting) with involvement from the entire Task Force, the ERSC, and the Science Team.

For KQ1, the working group considered available systematic reviews and decided to use the recent 2021 USPSTF review and their relevant key questions (KQ1 and KQ4) on the benefits and harms of hypertension screening as it aligns with the working group’s desired criteria and was judged to be of high quality using the AMSTAR-2 tool (Additional file 3) [89]. These 2021 USPSTF key questions will also be used to examine evidence on how benefits and harms vary by screening interval or age at screening (KQ1a) or, in the absence of data, what is the cumulative incidence of hypertension over different screening intervals and/or at different ages (KQ1b). The ERSC will not undertake updated searches of the USPSTF review. This topic does not have a rapidly evolving evidence base. To our knowledge, there have not been any screening trials published since the 2012 guideline that we would expect to change screening recommendations. Any additional new harms related to HBPM will be examined through targeted searches at the time of guideline development and will be addressed narratively. De novo systematic reviews will be conducted to address KQ2 and KQ4.

An overview of reviews will be undertaken to address KQ3. An overview approach was selected to maximize review efficiency, as there is a large evidence base of primary studies addressing treatment initiation for hypertension, as well as several high-quality systematic reviews that have summarized these primary studies. An overview approach will also enable us to explore concordance/discordance between existing systematic reviews in this area, where conflicting review results have previously been reported [95]. The methodology planned for the overview of reviews will be informed by the Cochrane Handbook (Chapter 5) [96], with additional supplementary guidance on overview methodology [97‐99]. To maximize efficiency and avoid duplication of efforts, we will use the National Institute for Health and Care Excellence (NICE, UK) 2019 review for initiating treatment of hypertension as the basis for our overview [100]. The KQ1 of the NICE review aligns with the working group’s desired criteria for KQ3, and the review captured systematic reviews of treatment initiation published since 2000. We will examine systematic reviews that were captured in the 2019 UK NICE review for inclusion (see the “Study selection” for further details on review selection) and search for any new systematic reviews that have been published since its conduct.

For KQ2 and KQ3, members of the working group developed a list of preliminary outcomes for key questions KQ2 and KQ3. For KQ1, outcomes were limited to those included in the 2021 USPSTF systematic review [89]. Through consensus, the outcomes for KQ1–KQ3 were rated by six working group members according to GRADE methodology as critical (rated 7 to 9 out of 9), important (rated 4 to 6 out of 9), or of limited importance (rated 1 to 3 out of 9) for making guideline recommendations [101]; only critical and important outcomes were retained for the systematic reviews. Outcomes related to KQ4 (acceptability) underwent a separate rating process.

The working group initially rated 11 outcomes as critical or important. Through consensus, it was decided that individual CVD-related morbidity outcomes would be collapsed into two categories: macrovascular CVD events (e.g., myocardial infarction, stroke, peripheral arterial disease) and microvascular complications (e.g., renal disease, retinal disease), thus collapsing into two versus five outcomes. Further, ‘overtreatment,’ although originally rated as an important outcome, was excluded given adverse effects of antihypertensive treatment, and overdiagnosis is already included. Therefore, a total of seven outcomes were included (see Table 2).

The inclusion and exclusion criteria for KQ1, KQ2, KQ3, and KQ4 are listed in Tables 3, 4, 5, and 6. The working group will rely on the 2021 USPSTF systematic review and their KQ1 and KQ4 on the benefits and harms of hypertension screening [89].

Draft search strategies (Additional file 4) have been developed by an experienced medical information specialist and tested through an iterative process in consultation with the review team. Prior to running the final searches, the MEDLINE strategies for each KQ will be peer reviewed by another senior information specialist using the PRESS checklist [102] (see Additional file 5). With the exception of the additional database, Epistemonikos, searched for KQ3, all databases will be searched on the Ovid platform in multifile mode, using the Ovid deduplication feature before downloading the results. Results will be downloaded and deduplicated using EndNote (Clarivate Analytics) and uploaded to DistillerSR.

We will supplement the electronic database search strategies with gray literature sources (i.e., sources other than peer-reviewed journals). We will follow the Canadian Agency for Drugs and Technologies in Health (CADTH) Grey Matters checklist [103] for relevant gray literature sources. The CADTH checklist includes health technology assessment agencies, guideline organizations, clinical trials registries, search engines, and additional databases. In addition to the CADTH checklist, we will search websites of relevant organizations as suggested by the working group and clinical experts. The full list of websites is available in Additional file 6.

Preprints will be eligible for inclusion in our de novo systematic reviews (KQ2/KQ4) and overview of reviews (KQ3) and handled based on the methodological considerations for use of preprints in evidence syntheses by Clyne and colleagues [104]. We will review bibliographic databases policies and coverage to ensure capture of relevant preprints. If preprints are included, we will check peer review status pre-specified intervals (full-text retrieval stage, results synthesis, search updates). If a final peer-reviewed version is found, we will check for differences between the preprint and the peer-reviewed version, and sensitivity analyses will be performed to assess the impact of inclusion of preprints on the overall review results and conclusions.

Search results will be downloaded and deduplicated using EndNote (Clarivate Analytics) [105]. Results will be uploaded into the DistillerSR (Evidence Partners, Ottawa, Canada) online screening and extraction platform [106]. Screening forms for title and abstract screening and full-text review will be developed and pilot tested on a random sample of 50 titles and abstracts and 25 full-text articles or five reviews for KQ3. Any disagreements among reviewers will be resolved by discussion, and adjustments to the form will be completed as required. Pilot testing will continue until the disagreement rate between reviewers is low (i.e., < 5%).

Title and abstract screening will be completed independently by reviewers using the liberal accelerated approach [107]. This approach allows records that one reviewer selects as either potentially relevant (i.e., included) or unclear about relevance to advance to full-text review without a second reviewer. Any record labelled as excluded will be screened by two reviewers to confirm the decision to exclude. Resolution about disagreements will not be required during this stage. Full-text review will be completed independently and in duplicate by reviewers. Any discrepancies will be resolved by consensus among the reviewers or by a third reviewer.

If articles are not available electronically, we will request access through the university library interlibrary loan service. Further, we will contact the corresponding author (by email with a maximum of three attempts) for published or unpublished reports or data. Similarly, we will search to see if a corresponding publication exists for protocols of potentially relevant studies that we identify. Otherwise, we will contact the corresponding author to determine the publication status. We will review the included studies of related evidence-based guidelines and knowledge syntheses that were identified as part of the scoping and refinement exercise and from the electronic database and gray literature searches.

If an article lacks sufficient information for us to decide on eligibility, we will contact the corresponding author for additional information (by email with a maximum of three attempts). If a response is not received, we will exclude the article. We may consult with the working group and clinical experts for advice on potentially eligible studies. When consulting with the working group, we will anonymize the article to avoid study and data identification. The decision on eligibility will be determined independently by the ERSC. For the excluded studies, we will provide a list of excluded studies with reasons for exclusion, and the study selection process will be documented in a PRISMA flow diagram [108].

We will develop standardized extraction forms in DistillerSR and pilot test the forms on a random sample of five included studies for each KQ [106]. Any data extraction differences among the reviewers will be resolved by discussion or consulting with a senior reviewer. Adjustments to the forms will be completed as appropriate. Data extraction will be completed independently and in duplicate by reviewers. Any discrepancies will be resolved by consensus among the reviewers or by a senior reviewer. The preliminary data extraction items for each KQ are available in Additional file 7. Data will be reformatted and presented in the text and tables of the final manuscript as needed. If information is missing or unclear, then we will contact the corresponding author of the study for the required information thrice by email over 1 month. For multiple publications of the same study, we will extract data from the most recent publication, and the previous publications will be used as secondary sources.

Forms for the risk-of-bias assessments will be developed in DistillerSR [106]. Reviewers will pilot test each study design form for a random sample of five included studies. Any conflicts among reviewers will be resolved by discussion or by a third reviewer. Assessments will be completed independently and in duplicate by reviewers using the appropriate study-specific tool for the design of the included study. Any disagreements in the assessments will be resolved by consensus among the reviewers or by a senior reviewer.

For the outcomes of interest, we will grade the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach [132, 133]. The GRADE framework involves rating (or grading) each of the following five domains for each outcome: study limitations (risk of bias), inconsistency or data heterogeneity, indirectness of evidence, imprecision of effect size estimates, and risk of publication (small study) bias. We will grade the five domains and then determine the overall certainty of the evidence for each outcome as either “very low,” “low,” “moderate,” or “high.” Trials (beginning at “high” certainty) and observational studies (beginning at “low” certainty) will be assessed separately.

The de novo systematic reviews will be reported using PRISMA (KQ2 and KQ4) [108], and overview of reviews (KQ3) will be reported using the Preferred Reporting Items for Overviews of systematic reviews including harms pilot checklist (PRIO-harms) [145].