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Abstract
Background High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD). Adequate treatment of high BP should reduce the risk of CVD, but this association has seldom been assessed in a general population setting.
Methods Population-based prospective study conducted in Lausanne, Switzerland, with a follow-up between 2003 and 2021. Participants were categorised as normal BP, untreated high BP, treated and uncontrolled BP and treated and controlled BP. Total and CVD mortality as well as any CVD event were assessed.
Results 5341 participants (65% normal, 17.4% untreated, 8.8% treated and uncontrolled and 8.8% treated and controlled) were included. After a median follow-up of 14 years (IQR: 11–15), 575 CVD events occurred. Relative to participants with normal BP, multivariable-adjusted HRs (and 95% CI) for total CVD were 1.38 (1.11 to 1.72) for untreated, 1.35 (1.04 to 1.76) for treated and uncontrolled and 1.50 (1.15 to 1.95) for treated and controlled. The corresponding HRs for CVD mortality (112 events) were 0.94 (0.52 to 1.70), 1.77 (1.00 to 3.12) and 2.52 (1.50 to 4.23), respectively. For total mortality (677 events), the HRs were 1.24 (1.01 to 1.52), 1.26 (0.99 to 1.60) and 1.27 (0.99 to 1.62), respectively. Sensitivity analysis using BP status during a 5-year period and categorising participants as always normal, always treated and uncontrolled, always treated and controlled and other led to similar findings.
Conclusion Over a long follow-up period of 14 years, BP control was not associated with reduction of CVD events, CVD-related or total mortality. This finding should help define further studies on factors affecting CVD and mortality in people treated for hypertension in the general population.
- hypertension
- risk factors
- global health
- epidemiology
Data availability statement
Data are available upon reasonable request. The data of CoLaus|PsyCoLaus study used in this article cannot be fully shared as they contain potentially sensitive personal information on participants. According to the Ethics Committee for Research of the Canton of Vaud, sharing these data would be a violation of the Swiss legislation with respect to privacy protection. However, coded individual-level data that do not allow researchers to identify participants are available upon request to researchers who meet the criteria for data sharing of the CoLaus|PsyCoLaus Datacenter (CHUV, Lausanne, Switzerland). Any researcher affiliated to a public or private research institution who complies with the CoLaus|PsyCoLaus standards can submit a research application to research.colaus@chuv.ch or research.psycolaus@chuv.ch. Proposals requiring baseline data only will be evaluated by the baseline (local) Scientific Committee (SC) of the CoLaus and PsyCoLaus studies. Proposals requiring follow-up data will be evaluated by the follow-up (multicentric) SC of the CoLaus|PsyCoLaus cohort study. Detailed instructions for gaining access to the CoLaus|PsyCoLaus data used in this study are available at www.colaus-psycolaus.ch/professionals/how-to-collaborate/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Hypertension is a major preventable cause of cardiovascular disease (CVD), which is the first cause of death globally.
Whether adequate management of high blood pressure (BP) levels over the years reduces CVD events and/or mortality in the general population remains an open debate.
WHAT THIS STUDY ADDS
This is one of the few population-based studies assessing the effect of BP status and BP trajectories on CVD events, CVD-related and all-cause mortality, with a long follow-up (up to 14 years).
Our study confirms that effective BP control remains suboptimal.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Management of hypertension per se appears to be insufficient to prevent CVD in the general population. A holistic approach on all CVD risk factors should be considered.
Introduction
Cardiovascular disease (CVD) is the first cause of death globally, accounting for over 17 million deaths annually.1 Hypertension is a major preventable cause of CVD and all-cause death.2 The global prevalence of hypertension was estimated to be 1.13 billion in 2015, with an estimated increase of 15%–20% by 2025.2 Despite the substantial progresses that have been made in understanding the epidemiology and pathophysiology of hypertension and effective treatment strategies, blood pressure (BP) control remains suboptimal worldwide.2–5 Evidence shows that lowering BP can substantially reduce premature morbidity and mortality,2 6 but whether inadequate management of BP levels is better than the absence of management remains an open debate. Studies failed to show the benefits of controlled versus uncontrolled hypertension on survival,7 8 whereas others suggested that treatment of hypertension could lead to worse prognosis than untreated hypertension.8 9
To investigate the role of BP control on cardiovascular outcomes and overall mortality in a general population with a long follow-up, we first aimed to assess the development of CVD according to BP status: normal, high untreated, treated and controlled, and treated and uncontrolled. Second, we assessed the development of CVD according to a 5-year BP trajectory. Our hypothesis was that people treated and controlled for hypertension would present a lower incidence of cardiovascular outcomes and mortality than people untreated or treated and uncontrolled.
Methods
Study setting
The CoLaus|PsyCoLaus study is a population-based study investigating the epidemiology and genetic determinants of psychiatric and CVD in Lausanne, Switzerland.10 Briefly, a representative sample was collected through a simple, non-stratified random sampling of 19 830 individuals (35% of the source population) aged between 35 years and 75 years. The baseline study was conducted between June 2003 and May 2006; the first follow-up was performed between April 2009 and September 2012; the second follow-up was performed between May 2014 and April 2017, and the third follow-up was performed between April 2018 and May 2021. Median follow-up time was 5.4 (average 5.6, range 4.5–8.8) years for the first follow-up, 10.7 (average 10.9, range 8.8–13.6) years for the second follow-up and 14.5 (average 14.6, range 13.2–17.3) for the third follow-up.
Blood pressure measurements and categorisation
BP was measured using an Omron HEM-907 (Kyoto, Japan) automated oscillometric sphygmomanometer after at least a 10 min rest in a seated position, and the average of the last two measurements was used. Hypertension was defined by systolic BP (SBP) ≥140 mm Hg or diastolic BP (DBP) ≥90 mm Hg or the presence of antihypertensive drug treatment.2 3 11 Antihypertensive drug treatment was assessed by asking the participants if they took medication against hypertension and by checking their prescribed medicines. Control of hypertension was considered for participants treated for hypertension and presenting with SBP <140 mm Hg and DBP<90 mm Hg.
For the first aim, four groups were created according to the BP status at baseline: (1) normal, (2) treated and controlled, (3) treated and uncontrolled and (4) untreated.
For the second aim, four groups were created according to the BP status at baseline and the first follow-up (online supplemental table 1): (1) normal untreated at both evaluations, (2) treated and controlled at both evaluations, (3) treated and uncontrolled at both evaluations and (4) other.
Supplemental material
Death and cardiovascular events
During the follow-up period, first incident CVD events and deaths were prospectively collected and independently adjudicated according to established recommendations and similar definitions detailed elsewhere.12 Details of the adjudication procedure are provided in online supplemental annex 1.
Other covariates
Smoking was self-reported and categorised as never, former (irrespective of the time since quitting smoking) and current. Education was categorised into high (university), middle (high school) and low (apprenticeship + primary). Marital status was defined as living alone (single, divorced or widowed) or living with a partner. Nationality was defined as Swiss or other. All drugs reported by the participants were collected and coded according to the Anatomical Therapeutic Chemical (ATC) classification.
Participants reported whether they currently consumed alcohol and how many standard drinks they had consumed in the past 7 days. Participants were then categorised according to the number of drinks per week: non-drinkers (0 drinks/week), moderate (1–13 drinks/week) alcohol consumption, high (14–34 drinks/week) alcohol consumption and very high (≥35 drinks/week) alcohol consumption.13 14
Body weight and height were measured with participants barefoot and in light indoor clothes. Body weight was measured in kilograms to the nearest 100 g using a seca scale (Hamburg, Germany). Height was measured to the nearest 5 mm using a seca (Hamburg, Germany) height gauge. Body mass index (BMI) was calculated and categorised as normal (<25 kg/m2), overweight (≥25 kg/m2 and <30 kg/m2) and obese (≥30 kg/m2).
Total cholesterol was assessed by CHOD-PAP, with maximum interbatch and intrabatch coefficient of variability (CVs) of 1.6% and 1.7%, respectively. High-density lipoprotein cholesterol was assessed by CHOD-PAP + polyethylene-glycol + cyclodextrin, with maximum interbatch and intrabatch CVs of 3.6% and 0.9%, respectively. Glucose was assessed by glucose dehydrogenase, with maximum interbatch and intrabatch CVs of 2.1% and 1.0%, respectively. Diabetes mellitus was defined as fasting plasma glucose ≥7.0 mmol/L and/or the presence of oral hypoglycaemic or insulin treatment. Hypolipidemic drug treatment was considered for any ATC code beginning with C10 (lipid-modifying agents).
Inclusion and exclusion criteria
For the first objective, participants were excluded if they (1) did not participate in the follow-up, (2) presented with previous CVD at baseline, (3) had missing data regarding medicines and (4) had missing data for any covariate.
For the second objective, participants were excluded if they (1) did not participate in the follow-up, (2) presented with previous CVD at the first follow-up, (3) had missing data regarding medicines and (4) had missing data for any covariate.
Ethical statement
The institutional Ethics Committee of the University of Lausanne, which afterwards became the Ethics Commission of Canton Vaud (www.cer-vd.ch), approved the baseline CoLaus study (reference 16/03). The approval was renewed for the first (reference 33/09), the second (reference 26/14) and the third (reference PB_2018–0 00 408) follow-ups. The approval for the entire CoLaus|PsyCoLaus study was confirmed in 2021 (reference PB_2018–00038, 239/09). The full decisions of the CER-VD can be obtained from the authors on request. The study was performed in agreement with the Helsinki Declaration and its former amendments and in accordance with the applicable Swiss legislation. All participants gave their signed informed consent before entering the study.
Statistical analysis
Statistical analyses were conducted using Stata V.16.1 (Stata Corp, College station, Texas, USA). Descriptive results were provided as the number of participants (percentage) for categorical variables and as average±SD or median (IQR) for continuous variables. Bivariate analyses were conducted using χ2 for categorical variables and Student’s t-test or Kruskal-Wallis test for continuous variables.
For both objectives, the association between BP categories and outcomes was assessed using Cox proportional hazard regression15 for total mortality and Fine-Gray competing risk model for CVD, using non-cardiac mortality as competing event.16 Results were expressed as HR and 95% CI. Multivariable analyses were adjusted for gender (man and woman), age (continuous), educational level (high, middle and low), smoking categories (never, former and current), BMI categories (normal, overweight and obese), alcohol consumption categories (non-drinkers, moderate, high and very high), diabetes (yes or no) and the presence of hypolipidemic drug treatment (yes or no).
As a sizeable fraction of the sample was excluded, we performed a sensitivity analysis using inverse probability weighting. Briefly, logistic regression was used to estimate the likelihood of being included for each participant using covariates that were significantly different between included and excluded participants. The inverse of the predicted probability was then used for the analysis of the associations between BP categories and outcomes.
Statistical significance was considered for a two-sided test with p<0.05.
Results
Blood pressure status and events: participant selection and characterisation
Of the initial 6733 participants, 5341 (79.3%) were included. The reasons for exclusion are presented in figure 1, and the comparison between included and excluded participants is provided in online supplemental table 2. Included participants were more frequently women, had a higher educational level, had a lower prevalence of obesity, were less frequently non-drinkers and presented less frequently with diabetes than excluded participants.
Selection of participants for the analysis between blood pressure at baseline and cardiovascular events and mortality, CoLaus study, Lausanne, Switzerland. BP, blood pressure; CVD, cardiovascular disease.
The characteristics of the participants according to BP status at baseline is presented in table 1. Participants with treated or untreated hypertension represented 35% of the sample. Among participants with hypertension, 49.8% were untreated, and among those treated, 50% were controlled. The four groups differed regarding age, gender distribution, educational level, BMI categories, smoking status, the prevalence of diabetes and hypolipidemic drugs, and lipid levels (table 1).
Baseline characteristics according to blood pressure status, CoLaus|PsyCoLaus study
Blood pressure status and events: bivariate and multivariable analyses
After a median follow-up of 14 years (IQR: 11–15), 575 CVD events (112 deaths) and 677 all-cause deaths occurred. The bivariate and multivariable associations between BP control and incidence of cardiovascular events and overall mortality are summarised in table 2. Compared with participants with normal, untreated BP levels, participants with treated or untreated hypertension had a higher risk of cardiovascular events, participants treated for hypertension had a higher risk of cardiovascular death irrespective of their control status and participants with untreated hypertension had a higher risk of death from all causes (table 2).
Prospective association between blood pressure control and cardiovascular events, CoLaus|PsyCoLaus study
Similar findings were obtained after inverse probability weighting, except that participants with treated and uncontrolled hypertension had a higher risk of death from all causes, while the association for participants with untreated hypertension was no longer statistically significant (online supplemental table 3).
Blood pressure trajectories and events: participant selection and characterisation
Of the initial 6733 participants at baseline, 4264 (63.3%) were included in the analysis between BP trajectories and events. The reasons for exclusion are indicated in figure 2, and the comparison between included and excluded participants is provided in online supplemental table 4. Included participants were younger, more frequently women, of higher education, more frequently born in Switzerland, of normal weight, never smokers, low-risk drinkers and presented less frequently with diabetes.
Selection of participants for the analysis between blood pressure trajectories and cardiovascular events and mortality, CoLaus study, Lausanne, Switzerland. BP, blood pressure; CVD, cardiovascular disease.
Most participants (56.3%) had consistently normal BP levels throughout the study period (‘always normal’ group). A small percentage (4.6%) had consistently treated and controlled BP, and a similar percentage (4.1%) had consistently treated but uncontrolled BP. The remaining participants (35.0%) fell into the ‘other’ category. Their clinical characteristics are summarised in table 3. Significant differences were observed across the BP trajectory groups: participants whose BP levels were always normal were younger, more frequently women, of higher education, more frequently of normal weight, current smokers, moderate-risk or high-risk drinkers and presented less frequently with diabetes or with hypolipidemic drug treatment.
Participants’ characteristics at the first follow-up according to blood pressure trajectories, CoLaus|PsyCoLaus study
Blood pressure trajectories and events: bivariate and multivariable analyses
The bivariate and multivariable associations between BP trajectories and incidence of cardiovascular events and overall mortality are summarised in table 4.
Association between blood pressure trajectories and cardiovascular events, CoLaus|PsyCoLaus study
After a median follow-up time of 9 years (IQR: 7–9.2), 325 CVD events (52 deaths) and 321 all-cause deaths occurred. On bivariate analysis, compared with participants with consistently normal BP levels, those in the ‘always treated and controlled’, ‘always treated and uncontrolled’ and ‘other’ groups exhibited higher incidence rates of cardiovascular events, cardiovascular death and overall mortality. After adjusting for potential confounding factors, the associations remained consistent, although not reaching statistical significance. Still, there was a trend towards higher incidence rates for all events in participants with consistently treated and uncontrolled BP, as well as in those classified in the ‘other’ category (see table 4). Further analysis performed using inverse probability weighting to account for excluded participants led to similar findings (see online supplemental table 5).
Discussion
The present study investigated the development of CVD and mortality in people according to their BP status and 5-year BP trajectory. People with hypertension had a significantly higher risk of developing CVD and CVD-related mortality that was not mitigated by antihypertensive drug treatment. Our findings also suggest that participants belonging to the ‘always treated and uncontrolled’ BP trajectory may experience a worse prognosis in terms of CVD, CVD-related death and overall mortality.
Blood pressure status and events
To our knowledge, our study is one of the few recent European investigations concerning persistent BP status and its association with CVD events. Our findings align with several previous studies (table 5). For instance, the study by Zhou et al in the USA found that participants with untreated or treated but uncontrolled hypertension had a higher risk of all-cause and CVD-related mortality compared with normotensive individuals.15 In our study, participants in the treated and controlled group had a higher hazard rate than reported in the same group by Zhou et al.15 A possible explanation might be the older age of our sample, as 56.9% were over 65 years old, versus 41.9% for the study of Zhou et al,15 although other unmeasured factors might intervene. Conversely, the HR for overall mortality in this study tended to be comparable with those of Zhou et al and Barengo et al, suggesting a consistent impact of BP status on general mortality outcomes across these diverse populations.15 17 Similarly, the study by Rojas et al in Cuba reported that participants with uncontrolled hypertension had an increased risk of all-cause and CVD-related mortality.5 A possible explanation for the lack of a protective effect of BP control would be that participants took their treatment just before coming to the clinical evaluation. Indeed, it has been shown that over one-fifth of patients temporarily discontinue their antihypertensive treatment which may have influenced our results.18 Another possible explanation is that our categorisation regarding high BP or BP control was based on a single measurement, which might have led to some misclassification of participants due to the white coat hypertension phenomenon. Still, white-coat hypertension has been suggested to be associated with an increased risk of CVD, which would explain the higher CVD risk observed among untreated participants.19 Interestingly, in elderly individuals, the relationship between BP and health outcomes is more complex. Anker et al demonstrated that low BP in frail older adults might be associated with worse health outcomes.20 Smitson et al revealed that declining BP trajectories on elderly individuals were linked to an increased risk of mortality and higher rates of CVD.21 This notion aligns with the findings from other studies that highlighted the potential risk of very low DBP, emphasising the importance of considering both SBP and DBP levels for optimal cardiovascular health.22 23 Overall, these studies highlight the intricate relationship between BP, frailty and health outcomes in elderly patients, potentially elucidating the reasons behind our inability to demonstrate a protective effect of BP reduction.
Blood pressure trajectories and events
No significant association was found between BP trajectories and CVD or overall mortality. Several studies have explored the relationship between BP trajectories and cardiovascular outcomes, and no consensus could be found. The study by German et al used data from the Systolic Blood Pressure Intervention Trial to identify four distinct SBP trajectories.24 The authors found that participants with uncontrolled BP levels had a worse prognosis regarding CVD events and all-cause mortality, irrespective of their baseline BP. A study by Smitson et al on US elderly identified three distinct BP trajectory groups, participants with declining BP trajectories presenting an increased mortality risk compared with those with stable or increasing trajectories.21 Finally, the study by Barengo et al observed a significant increase in all-cause mortality among treated hypertensive participants who had only their SBP or DBP controlled.17 Overall, there is a lack of consensus regarding whether adequate management of high BP levels reduces CVD events in the general population, and it would be important that other studies are conducted to clarify this issue. Table 6 compares the results of studies analysing BP trajectories and CVD and mortality. In most cases, persistent high BP or increasing BP was associated with an increased risk of CVD, and control of BP was not systematically associated with a decreased risk of CVD.
Comparative overview of results between the current study and previous studies analysing blood pressure trajectories and CVD and mortality
Implications for clinical practice
An important finding of this study is that approximately half of the hypertensive subjects fell into the ‘always treated and uncontrolled’ group, which is consistent with other studies.25 26 This highlights the need for healthcare providers to improve BP management and achieve better control among their patients. It is crucial for clinicians to recognise that simply prescribing antihypertensive medications might not be sufficient.2 25 Ensuring that patients adhere to their treatment regimens and regularly monitoring and adjusting their BP levels are vital steps in optimising long-term cardiovascular health.
Strengths and limitations
This is one of the few population-based studies assessing the effect of BP status and BP trajectories on CVD events, CVD-related and all-cause mortality. Its long follow-up time allowed a reasonable number of events to occur and thus to assess the BP trajectories for a significant number of participants. Additionally, CVDs were meticulously collected and adjudicated and were not based on sole medical diagnosis or the international classification of diseases.
Several limitations should also be considered when interpreting the results. First, BP status and trajectories were based on single assessments, which could lead to misclassification of participants’ BP status. This could partly explain the lack of association between untreated participants and cardiovascular events. Indeed, untreated subjects might have been falsely diagnosed as hypertensive and presented lower levels of obesity, diabetes and hypolipidemic treatment. Further studies should rely on a more precise evaluation of BP such as ambulatory BP monitoring. Second, it was not possible to account for treatment discontinuation before or during the study assessments, as it has been shown that approximately 22% of patients temporarily discontinue their antihypertensive treatment.18 Third, our study was limited to an urban, mainly Caucasian population living in a high-income country, and it would be of interest if our results also apply to other settings. Fourth, one-fifth of the sample was excluded, which could have biased the results. Still, the results were similar after inverse probability weighting to account for exclusion. Finally, it was not possible to consider other potential confounding factors such as diet or physical activity. Hence, the issue of residual confounding cannot be ruled out.
Conclusion
In this population-based prospective study, participants with untreated or uncontrolled BP levels had a higher risk of CVD events and mortality (for untreated) than participants with normal BP levels. No significant benefit of BP control was found regarding CVD events, CVD-related or total mortality. BP trajectories were unrelated to CVD events, CVD-related or total mortality.
Data availability statement
Data are available upon reasonable request. The data of CoLaus|PsyCoLaus study used in this article cannot be fully shared as they contain potentially sensitive personal information on participants. According to the Ethics Committee for Research of the Canton of Vaud, sharing these data would be a violation of the Swiss legislation with respect to privacy protection. However, coded individual-level data that do not allow researchers to identify participants are available upon request to researchers who meet the criteria for data sharing of the CoLaus|PsyCoLaus Datacenter (CHUV, Lausanne, Switzerland). Any researcher affiliated to a public or private research institution who complies with the CoLaus|PsyCoLaus standards can submit a research application to research.colaus@chuv.ch or research.psycolaus@chuv.ch. Proposals requiring baseline data only will be evaluated by the baseline (local) Scientific Committee (SC) of the CoLaus and PsyCoLaus studies. Proposals requiring follow-up data will be evaluated by the follow-up (multicentric) SC of the CoLaus|PsyCoLaus cohort study. Detailed instructions for gaining access to the CoLaus|PsyCoLaus data used in this study are available at www.colaus-psycolaus.ch/professionals/how-to-collaborate/.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Ethics Commission of Canton Vaud (reference PB_2018-000408). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Panagiotis Antiochos, Cédric Gubelmann, Marylène Bay, Benoît Delabays, Guillaume Jordan, Adelin Barrier and Gérard Waeber.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors YC: investigation, formal analysis, writing—original draft—and visualisation. MR: investigation. PV: review and editing. JV: conceptualisation and writing—review and editing. P-MM-V: conceptualisation, data curation, validation, writing—review and editing—and supervision. P-MM-V accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding The CoLaus|PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, 33CS30-148401, 33CS30_177535 and 3247730_204523) and the Swiss Personalized Health Network (grant 2018DRI01). The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note JV and P-MM-V are joint last authors.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.