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The link between adherence to antihypertensive medications and mortality rates in patients with hypertension: a systematic review and meta-analysis of cohort studies

BMC Cardiovascular Disorders volume 25, Article number: 145 (2025) Cite this article

Abstract

Background

Hypertension (HTN) significantly contributes to cardiovascular disease (CVD) and mortality. This systematic review and meta-analysis specifically investigates how different levels of adherence to antihypertensive therapy (AHT) affect mortality rates in HTN patients. By synthesizing cohort studies, it aims to enhance understanding and inform clinical practices to improve outcomes in hypertensive populations.

Methods

Our meta-analysis employed a comprehensive search strategy using keywords related to hypertension, medical adherence, and mortality across PubMed, Scopus, and Web of Science, up to July 2024. The eligibility criteria focused on cohort studies linking AHT adherence to mortality. The Newcastle–Ottawa Scale (NOS) was used to assess the risk of bias (ROB). Quantitative analyses involved hazard ratios (HR) and confidence intervals (CI), with an 80% adherence threshold. Subgroup and meta-regression analyses were also conducted using STATA-17 to explore various outcome factors.

Results

From initial 1,999 studies 12 cohort studies included in our analysis. All included studies had low ROB score. A meta-analysis of 12 studies involving 2,198,311 patient with HTN revealed that poor adherence to treatment significantly increased all-cause mortality (HR: 1.32 [1.14, 1.51], p < 0.001) with high heterogeneity (I²: 98.73%). Additionally, an analysis of four studies with 1,695,872 patients indicated that low adherence was linked to elevated cardiovascular mortality (HR: 1.61 [1.43, 1.78], p < 0.001), showing moderate heterogeneity (I²: 49.51%).

Conclusions

The study found that poor adherence to AHT significantly increases overall and cardiovascular mortality risk, underscoring the need for improved compliance strategies. Limitations like inconsistent definitions, observational biases, and varying follow-up durations necessitate further research to validate these findings.

Clinical trial number

Not applicable.

Peer Review reports

Introduction

Hypertension (HTN) remains a leading global health issue, contributing significantly to morbidity and mortality rates worldwide. In 2019 it is estimated that high blood pressure accounts for over 0.85 million deaths and 14.56 million disability-adjusted life-years annually [1]. Medication adherence is defined as the degree to which patients follow their prescribed medication regimens [2]. Despite hypertension being one of the most prevalent chronic conditions and a significant global health threat, medication nonadherence among patient with HTN remains alarmingly high [3]. Research indicates that nearly 50% of patients discontinue antihypertensive medications within the first year, complicating global blood pressure management. Less than one-third of patients in high-income countries and only one-tenth in low- and middle-income nations achieve optimal blood pressure, contributing to rising cardiovascular diseases and mortality worldwide [4,5,6].

Clinical trials have shown that consistent use of antihypertensive medications (AHM) successfully lowers blood pressure in many patients, resulting in substantial reductions in cardiovascular-related morbidity and mortality [7]. Cardiovascular diseases (CVDs) represent a significant global health challenge, with the Global Burden of Disease Study indicating that over 485.6 million individuals were affected by these conditions in 2017. CVDs are also the leading cause of death worldwide, responsible for more than 17.79 million fatalities, which accounts for 31.8% of all deaths globally. This alarming prevalence underscores the urgent need for effective strategies to mitigate the incidence of CVD events [8,9,10].

In contrast, nonadherence to medication, which refers to the extent that patients do not follow their healthcare provider’s recommendations regarding medication use, hinders the effectiveness of treatments aimed at managing cardiovascular risks [11, 12]. The World Health Organization (WHO) identifies various factors contributing to nonadherence, including socioeconomic aspects like age, gender, and education; patient-specific traits such as willingness to change and self-confidence; treatment complexities; coexisting health conditions; and healthcare system challenges like doctor-patient relationships and physician burnout [13, 14].

AHT markedly decreases the morbidity and mortality associated with cardiovascular disease, as evidenced by various randomized controlled trials (RCTs) [15,16,17]. Following AHT guidelines significantly lowers the risk of mortality; in contrast, nonadherence increases all-cause mortality by 1.57 times and the likelihood of cardiovascular hospitalization by 1.25 times [18]. Furthermore, a recent investigation revealed that each percentage point rise in adherence is linked to a decrease of approximately 7.13 cardiovascular deaths per 100,000 individuals [19]. Many studies have found that adherence to AHT reduces both all-cause mortality and CVD mortality among patient with HTN [20, 21]. However, the relationship between adherence to AHT and mortality is complex; some research presents neutral findings, suggesting a need for further investigation [22, 23]. High adherence to AHT leads to better health outcomes, significantly reducing complications like stroke and heart failure, with intervention adherence rates reaching 98.63% versus 49.14% in controls [24].

This systematic review and meta-analysis is the first to explore how sticking to AHT affects mortality rates in patients with HTN. By looking at various cohort studies, the research aims to fill important knowledge gaps and provide valuable insights for better managing HTN. A more specific focus on how AHT adherence influences overall and CVD mortality could clarify these relationships. Ultimately, this work seeks to enhance patient outcomes by improving adherence strategies in clinical practice.

Methods

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 [25] (its checklist in Supplementary Material 1). The registration number in PROSPERO is CRD42024592893.

Search strategy

The final search keywords comprised three primary terms: Hypertension, Medical Adherence, and Mortality (Search using AND for every three main terms, and use OR for synonyms within each main term). All relevant synonyms and MESH terms were utilized to develop the most effective search strategy. Three databases—PubMed, Scopus, and Web of Science— were searched for English-language records until July 2024 without any restrictions based on time or age. Additionally, grey literature was explored through manual searches on Google Scholar and by reviewing the references of all included studies (detailed search information for the databases can be found in Supplementary Material 1).

Eligibility criteria

We conducted a systematic review and meta-analysis of cohort studies that investigated the relationship between adherence to antihypertensive therapy (AHT) and mortality rates among individuals diagnosed with hypertension. The primary exposure of interest was the consumption of antihypertensive medications, while the outcomes were all-cause mortality and cardiovascular (CV) mortality. Studies were excluded from the analysis if they lacked sufficient data (absence of the report detailing the effect size in a format suitable for analysis extraction) for statistical evaluation or employed study designs other than cohort studies.

Study selection and data extraction

Two researchers independently reviewed the titles and abstracts of potentially relevant studies to determine eligibility. For the studies that passed this initial screening, different researchers separately assessed the full texts. Any disagreements about study design, methodology, or the final decision to include a study were resolved through a consensus meeting involving all the review authors. The same two original researchers then independently extracted data from the selected articles. They collected the following general characteristics for each study: Author, Country, Number of Participants, Percentage of Male, Medical Adherence Tool Used, Condition (Hypertension), Follow-up Duration (in years), and NOS Score (presented in Table 1).

Table 1 Overall characteristics of all included studies
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Risk of bias (ROB) assessment

Two investigators independently conducted a quality assessment using the Newcastle–Ottawa Quality Scale (NOS) to evaluate the risk of bias (ROB) in the included cohort studies [26], which were classified as having a low (≥ 7 stars), moderate (5–6 stars), or high ROB score (≤ 4 stars), with an overall quality score of 9 stars; any discrepancies were resolved through discussion and consensus, including a third investigator if needed.

Quantitative analysis

To determine the final effect size, we utilized hazard ratio (HR) and standard error (SE) statistics. To standardize the HR reported in the studies, we classified medical adherence as good if it was over 80% and poor if it was below that threshold; in some studies, the groups with poor adherence were combined. A random effects model, specifically the restricted maximum likelihood model, was employed to aggregate the extracted HR values. We assessed heterogeneity among the studies using the chi-square test and the I-squared statistic. Publication bias was evaluated through Begg and Egger tests, along with a funnel plot. Additionally, a sensitivity analysis was conducted to examine the reliability of the pooled effect size. A subgroup analysis was carried out to estimate the pooled effect based on factors such as nationality, total population, mean age, percentage of males, assessment tool, diagnosis, and follow-up duration. Meta-regression was performed considering the publication year, mean age, percentage of males, and follow-up duration. All analyses were conducted using Stata-17 software, with p-values below 0.05 deemed statistically significant.

Results

Study selection

From an initial set of 1,999 records retrieved from databases, 793 duplicate records were removed. Of the remaining 1,206 records, 1,133 were excluded based on title and abstract screening. After full-text review of 73 articles, 12 studies [7, 12, 18, 20, 21, 23, 27,28,29,30,31] were ultimately included in the analysis (Fig. 1).

Fig. 1
figure 1

PRISMA flow diagram of all included studies

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Characteristics of studies

In total thirteen cohort studies with total 2,198,311 HTN patients included in our studies. The studies involved a wide range of participants, from as few as 2,199 in Canada to over 1.6 million in South Korea. The percentage of male participants varied significantly, with the highest at 91.4% in a US study by Gosmanova et al. and the lowest at 45.1% in a study from Hong Kong by Wong et al. Different tools were employed to assess adherence, including the Proportion of Days Covered (PDC), Medication Possession Ratio (MPR), and Visual Analog Scale (VAS). The most commonly used tool across studies was PDC, utilized in six out of the ten studies. The studies differentiated between newly treated and older patients. Most studies focused on newly treated patients, with only three studies examining old HTN patients. Follow-up periods varied, ranging from 1 year (Shin et al. 2013) to 10 years (Lee et al. 2019) (Table 1).

ROB

All studies were assessed as having low ROB. Ten of the studies achieved a NOS score of eight, indicating a low risk of bias. Additionally, two other studies also received the same NOS score of seven (Table 1).

Synthesis of results

All-cause mortality

In a meta-analysis of all-cause mortality related to adherence, 12 studies encompassing 15 effect sizes and a total of 2,198,311 patients with hypertension were examined. The findings indicated that poor adherence was linked to an increased mortality rate (HR: 1.32 [1.14, 1.51], p < 0.001), exhibiting considerable heterogeneity (I²: 98.73%) (Fig. 2). A sensitivity analysis revealed that excluding any individual study did not significantly alter the overall effect size. Additionally, funnel plots and the Egger (p = 0.95) and Begg (p = 0.10) tests indicated no evidence of publication bias (Fig. 3).

Fig. 2
figure 2

Meta-analysis of the all-cause mortality related to adherence to antihypertensive medication in patient with HTN

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Fig. 3
figure 3

Funnel plot of the all-cause mortality related to adherence to antihypertensive medication in patient with HTN

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A subgroup meta-analysis was conducted based on various factors including nationality, total population, mean age, percentage of males, assessment tools, diagnosis, and follow-up duration. Most subgroups showed non-significant results, with the exception of the diagnosis category. The analysis indicated that newly treated patients had a lower hazard ratio (HR: 1.22 [1.07, 1.37]) compared to those who had been on antihypertensive medication for a longer time (HR: 1.75 [1.33, 2.18]) (p = 0.02), as detailed in Fig. 4. Furthermore, a meta-regression analysis was performed considering publication year, mean age, percentage of males, and follow-up duration. All factors were found to be non-significant, except for the publication year, which positively influenced the hazard ratio (0.049) with statistical significance (p = 0.012) and a 95% confidence interval of (0.011, 0.088) (see Table 2; Fig. 5).

Fig. 4
figure 4

Subgroup meta-analysis of the all-cause mortality related to adherence to antihypertensive medication in patient with HTN

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Table 2 Meta regression of the studies based on variables
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Fig. 5
figure 5

Bubble Plot for Meta-Regression of Desired Variables

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CV mortality

In a thorough examination of CV mortality associated with adherence, four studies were analyzed, which included four effect sizes and a total of 1,695,872 patients with hypertension. The results showed that low adherence was associated with a higher rate of CV mortality (HR: 1.61 [1.43, 1.78], p < 0.001), with moderate heterogeneity observed (I²: 49.51%) (Fig. 6). A sensitivity analysis demonstrated that removing any single study did not significantly impact the overall effect size. Furthermore, funnel plots along with the Egger (p = 0.44) and Begg (p = 0.73) tests indicated no signs of publication bias (Fig. 7).

Fig. 6
figure 6

Meta-analysis of the cardiovascular mortality related to adherence to antihypertensive medication in patient with HTN

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Fig. 7
figure 7

Funnel plot of the cardiovascular mortality related to adherence to antihypertensive medication in patient with HTN

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A subgroup meta-analysis was conducted based on various factors including total population, mean age, percentage of males, assessment tools, and diagnosis. Most subgroups showed non-significant results, with the exception of the diagnosis category. The analysis indicated that newly treated patients had a lower hazard ratio (HR: 1.53 [1.49, 1.57]) compared to those who had been on antihypertensive medication for a longer time (HR: 1.80 [1.57, 2.03]) (p = 0.02), as detailed in Fig. 8.

Fig. 8
figure 8

Subgroup meta-analysis of the cardiovascular mortality related to adherence to antihypertensive medication in patient with HTN

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Discussion

This systematic review and meta-analysis provide strong evidence linking AHT with mortality rates in patients with HTN. Analysing 12 studies involving over 2 million patients, the results indicated that poor adherence is significantly associated with an higher risk of all-cause mortality, reflected by a HR of 1.32. This discovery highlights the essential importance of AHT in successfully managing hypertension, as nonadherence not only jeopardizes blood pressure regulation but is also linked to a higher risk of CV complications and increased mortality. The considerable heterogeneity observed across studies suggests variability in patient populations, adherence measurement methods, and follow-up durations, warranting further investigation into these factors. The subgroup analysis showed that patients on long-term AHT had a higher mortality risk (HR: 1.75) compared to newly treated patients (HR: 1.22), likely due to the cumulative effects of poor adherence and worsening complications over time. Newly treated patients may have better adherence initially due to closer follow-up or motivation. The meta-regression further indicated that the adverse effects of poor adherence have intensified in more recent years.

In terms of CV mortality, the analysis of four studies [20, 21, 29, 30] with nearly 1.7 million patients revealed that low adherence correlates with a significantly higher rate of CV mortality (HR: 1.61). The subgroup analysis for CV mortality mirrored the results seen in all-cause mortality, with newly treated patients having a lower hazard ratio (HR: 1.53) compared to those on longer-term treatment (HR: 1.80). This finding underscores the urgency of addressing non-adherence early in the treatment course to prevent the compounding risks associated with chronic hypertension and its complications.

Overall, this study underscores the necessity of enhancing medication adherence to improve health outcomes and reduce mortality rates among patient with HTN. Our meta-regression analysis revealed that while several factors such as total population size and mean age were non-significant, the year of publication positively influenced the hazard ratio (p = 0.012). This suggests that recent advancements in hypertension management and increased awareness of the importance of medication adherence may have contributed to improved outcomes over time.

Following antihypertensive therapy can look very different depending on cultural backgrounds and healthcare systems. Factors like cultural beliefs, understanding of health, and communication between patients and providers greatly affect how well people stick to their medication. In diverse places like Singapore, language barriers and cultural views on medicine can create challenges [32]. Additionally, research shows that ethnic minorities, especially Black patients, tend to struggle with sticking to their treatment plans. This often stems from limited understanding of their condition and poor communication with healthcare providers [33]. Effective antihypertensive therapy is essential for managing hypertension and preventing cardiovascular diseases, making cultural competence in healthcare delivery vital for improving patient outcomes [34, 35].

Current guidelines recommend a target office blood pressure of less than 140/90 mm Hg for treatment, irrespective of cardiovascular risk or comorbidities. Recent meta-analyses indicate that a 10 mm Hg reduction in systolic blood pressure significantly lowers the risk of major cardiovascular events [16, 36]. However, studies by Benegas JR et al. and Chow CK et al. reveal that fewer than 50% of patients reach the target systolic blood pressure of < 140 mm Hg [37, 38].

Non-adherence to medication is a significant factor in the failure to manage hypertension effectively within the general population. Identifying and assessing non-adherence in clinical settings poses challenges [39]. Methods used to address this issue typically rely on indirect indicators, such as pill counts, pharmacy records, or blood pressure measurements, rather than concrete outcomes like major adverse cardiovascular events. However, pill counts can be unreliable, and patients frequently forget to bring their medication containers to appointments [40]. While pharmacy records demonstrate good validity, they are infrequently utilized due to various professional, acceptability, and organizational challenges [41]. Despite the well-documented importance of blood pressure management in preventing CVD and mortality, as shown in earlier studies [42,43,44,45], there remains limited evidence at the clinical level linking adherence to antihypertensive medication with clinical outcomes.

In contrast, studies included in our analysis have found a positive relationship between medication adherence and clinical outcomes, such as the risk of all-cause mortality and cardiovascular events [7, 22, 42], underscoring the significance of sustaining optimal medication adherence. Research indicates a significant link between low adherence to antihypertensive medications and insufficient blood pressure control, resulting in an increased risk of cardiovascular events [46,47,48,49]. Research by Bramley TJ et al. found that high adherence (medication possession ratio of 80–100%) was associated with better odds of achieving blood pressure control compared to lower adherence levels [50]. Another study showed that strong adherence to antihypertensive medication significantly reduced cardiovascular events in primary prevention [51].

A recent meta-analysis confirmed that good adherence lowers the risk of stroke [52], and another indicated that high adherence is linked to lower mortality risk [53]. Ho et al. [54] explored the link between CVD mortality and adherence in coronary artery disease patients, revealing that nonadherence increased both CVD and all-cause mortality risks. Interestingly, the increase in all-cause mortality risk (e.g., HR = 1.50 for beta-blockers, HR = 1.74 for ACE inhibitors) was greater than the rise in CVD hospitalization risk (HR = 1.10 for beta-blockers, HR = 1.40 for ACE inhibitors). Other studies supported these findings, showing that low adherence results in a higher risk of all-cause mortality compared to CVD-related hospitalization [55, 56]. In comparison, the adherence to medications in other diseases has also been investigated. For example, in a meta-analysis of 39 studies involving 2,117,789 participants found that medication non-adherence in patients with atrial fibrillation, hyperlipidaemia, hypertension, and type 2 diabetes mellitus, all without prior stroke, significantly increased the risk of stroke and stroke-related mortality, emphasizing the need for improved adherence in primary stroke prevention [57].

In addition, a prospective cohort study of 785 patients with diabetes and peripheral arterial disease found that non-adherence to both medications and lifestyle recommendations significantly increased the risk of one-year all-cause mortality and major adverse cardiovascular events, highlighting the importance of adherence in secondary prevention efforts [58].

Limitation and strength

The study boasts several strengths. It is the first meta-analysis to systematically evaluate this relationship, providing a comprehensive overview of existing literature. By employing a consistent cutoff for adherence scores, it enhances comparability across studies, allowing for more robust conclusions. The inclusion of subgroup analyses and meta-regression facilitates the exploration of heterogeneity among studies, revealing patterns that might otherwise remain obscured. Furthermore, the analysis is supported by a large sample size, increasing statistical power and the reliability of findings, thereby contributing valuable insights into the impact of medication adherence on mortality rates in patient with HTN.

The study has several limitations. Firstly, it primarily draws data from a limited number of countries, which may impact the generalizability of the findings across diverse populations. Additionally, the variability in definitions of medication adherence among included studies complicates comparisons and synthesis of results. The observational design of these studies introduces potential biases, such as confounding variables that could influence both adherence and mortality outcomes; We also included the cohort studies that introduce certain biases which may influence the study’s results. Moreover, differences in follow-up durations and methodologies across studies may lead to inconsistent data regarding the long-term effects of adherence on mortality rates. Another limitation regarding cardiovascular mortality is the small number of included studies (four), which may elevate the risk of Type II errors, resulting in false negatives and missed significant effects. However, due to the strong significance of the results, a larger analysis might confirm these findings, as indicated by the primary study. Finally, the results show a high degree of heterogeneity, likely influenced by numerous confounding variables such as sociodemographic and cultural factors. Controlling for these variables is challenging and requires extensive research in each specific context.

Future research should assess this correlation in various settings with diverse socioeconomic and cultural contexts that may affect outcomes, incorporating additional factors influencing mortality beyond AHT. Moreover, interventions to enhance adherence should be tailored to the specific context of the study. For instance, effective strategies include patient education [59], simplifying medication regimens with single-pill combinations [60], involving pharmacists for support, and utilizing digital tools like smartphone apps [61] for reminders and adherence tracking, all of which promote understanding and motivation.

Conclusions

In conclusion, this systematic review highlights a clear link between adherence to antihypertensive medications and mortality rates among patients with hypertension. Given the substantial burden of cardiovascular disease related to poor medication adherence, healthcare providers must prioritize strategies aimed at improving patient adherence to treatment regimens. Future research should focus on identifying effective interventions tailored to enhance adherence, particularly in populations at higher risk for nonadherence, such as those newly initiated on antihypertensive therapy. By addressing these challenges, we can improve health outcomes and reduce mortality rates in patient with HTN globally.

Data availability

No datasets were generated or analysed during the current study.

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  1. Department of Cardiology, First Hospital of Fangshan District, No 6 Fangyao Road, Chengguan Fangshan District, Beijing, 102400, China

    Xuemei Peng, Lihong Wan, Benkai Yu & Jianhui Zhang

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XP and LW were involved in developing the hypothesis, gathering and analyzing data, writing the manuscript, and creating tables and figures. JZ contributed to the hypothesis, engineered and edited the collected data, handled correspondence, and revised the manuscript prior to submission.

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Peng, X., Wan, L., Yu, B. et al. The link between adherence to antihypertensive medications and mortality rates in patients with hypertension: a systematic review and meta-analysis of cohort studies. BMC Cardiovasc Disord 25, 145 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12872-025-04538-6

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Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

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