Abstract
Objective
To assess the association between the blood pressure (BP) reduction mediated by BP-lowering agents and the risks of peripheral arterial disease (PAD) in patients with cardiometabolic risk factors.
Methods
PubMed, EMBASE, the Cochrane Centre Register of Controlled Trials for Studies, the Scopus, Web of Science and Clinicaltrial.gov were searched from January 1980 to October 2023. Randomized controlled trials (RCTs) with statistically significant BP reduction in intensive BP-lowering treatments group compared with control treatment group, reporting the incidence of PAD were included. Regular and dose-response meta-analyses were both conducted.
Results
In all, 15 RCTs involving 94482 participants were included. The standardized analysis based on systolic blood pressure (SBP) reduction revealed that each 10 mmHg reduction in SBP mediated by BP-lowering agents was associated with a 37% increase in the risk of PAD in patients with cardiometabolic risk factors (RR = 1.37, 95% CI 1.08 to 1.74). The difference of the SBP reduction from baseline between the intensive anti-hypertensive treatment group and the control group was associated with the increased risk of PAD (β=-0.1107, 95%CI, −0.219 to −0.002, p = 0.047). Dose-response analysis further confirmed a linear association between SBP reduction and the risk of PAD in patients with cardiometabolic risk factors, with a 3.22% increase in risk for every 1 mmHg decrease in SBP (RR = 1.032, 95% CI 1.008 to 1.057, p = 0.009).
Conclusion
Our meta-analysis revealed that intensive reductions in SBP mediated by BP-lowering agents conferred increase the risk of PAD in patients with cardiometabolic risk factors. A gradual and moderate BP reduction as well as regular BP monitoring should be recommended for patients at high risk of PAD.
Keywords: Peripheral arterial disease, diabetes, blood pressure–lowering agents, hypertension
Introduction
Peripheral artery disease (PAD) is an atherosclerotic disease of the lower extremities [1]. The estimated global population with PAD grew by 72% between 1990 and 2019, from 65,764,499 to 113,443,016 [2]. Evidence suggests that smoking, diabetes, hypertension and hypercholesterolemia are major risk factors. Thus, effective management of blood pressure (BP) and blood glucose levels is emphasized in reducing the risk of PAD. For patients with PAD, BP management targets of <130/80 mmHg has been recommended by the American Heart Association for cardiovascular protection [3].
In individuals with PAD, narrowed or blocked blood vessels supplying oxygen and nutrients to the legs and feet can lead to reduced blood flow and serious complications such as limping, diabetic foot, or even amputation. Noteworthy, the hemodynamic changes caused by BP lowering agents may also influence the occurrence and progression of PAD [4]. It is believed that hypertension exacerbates endothelial cell damage, accelerating the development of PAD. Therefore, BP lowering agents may alleviate mechanical damage to blood vessels, consequently reducing the risk of PAD.
However, recent analyses have revealed contradictory findings regarding the association between BP levels and the risk of PAD. One study involving 4.2 million relatively healthy adults found that an increase in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) was associated with a higher incidence of PAD events [5]. On the other hand, a reanalysis of ALLHAT study suggested that a higher incidence of lower extremity PAD events was associated with both lower and higher SBP, as well as lower DBP [6].
Our previous research found that weight loss and reductions in SBP mediated by sodium glucose co-transporter 2 inhibitors (SGLT-2i) were associated with an increased risk of PAD and its related events (including amputation and DF) in individuals with T2D [7]. The reduction in blood volume caused by the diuretic effect of SGLT2i may undermine the circulation of the distal peripheral arterial bed, thus aggravating peripheral ischemia and promoting the occurrence of lower limb complications in susceptible patients [7].
Presently, the existing evidence is inconsistent, and the relationship between BP lowering agents and the risk of PAD remains unclear [8,9]. Therefore, we designed and conducted a systematic review and meta-analysis to investigate whether significant reductions in BP mediated by BP lowering agents would modify the risk of PAD.
Methods
This systematic review and meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study has been registered with ID CRD42021285866 on PROSPERO.
Data sources and searches
According to recommendations from the Cochrane Handbook, two independent investigators (Xingyun Zhu and Ruoyang Jiao) searched Pubmed, Embase, the Cochrane Center Register of Controlled Trials for Studies, the Scopus and Web of Science and Clinicaltrial.gov for RCTs from the inception during January 1980 and October 2023. Details of the search strategy are shown in the (supplementary material Table S1).
Study selection and eligibility criteria
Two independent reviewers (Xingyun Zhu and Ruoyang Jiao) performed the title and abstract screening to identify potentially eligible studies. After the initial screening, full-text articles were retrieved and assessed for eligibility based on the following criteria: (1) RCTs with statistically significant BP reduction between intensive BP lowering agent group and placebo or active comparator treatment group (intensive BP lowering agent group referred to a intervention group where patients received more aggressive antihypertensive therapy compared to the standard treatment group and achieved greater BP reduction with statistical significance); (2) RCTs conducted in population with cardiometabolic risk factors (hypertension, heart failure, cardiovascular disease and diabetes) and requiring anti-hypertensive medications; (3) RCTs with the reports of PAD events. The full-text screening process followed the same procedure as the title and abstract screening, with disagreements resolved by discussion with a third reviewer (Xiaoling Cai).
Data extraction and quality assessment
Two investigators (Xingyun Zhu and Chu Lin) independently abstracted and checked data of all studies, including the publication details, study design, treatment arms, study duration, population characteristics, diabetes proportion, baseline SBP level, baseline DBP level, SBP changes between groups, DBP changes between groups, PAD events. Definition of PAD was shown in Table S2. The PAD events analysed in this study were primarily exacted from original publications. If the data were absent in both articles and supplementary materials, the number of PAD events would be extracted from Clinicaltrial.gov website with unique registered RCT number. Two reviewers (Xingyun Zhu and Chu Lin) assessed the risk of bias in enrolled studies using the Cochrane risk of bias tool and RoB2 tool. Discrepancies would be resolved by joint discussions with another investigator (Xiaoling Cai) by reaching a consensus.
Data synthesis and analysis
The primary outcome of this meta-analysis was the association between the significant BP reduction mediated by BP-lowering agents and the risk of PAD in patients with cardiometabolic risk factors and requiring anti-hypertensive medications. Subgroup analyses were performed according to the drug types of BP-lowering agents. Continuous variables were computed as weighted mean difference (WMD) and the corresponding 95% CI in random effect model. Categorical variables were calculated as the risk ratios (RRs) and the corresponding 95% CI. The between-study heterogeneity was evaluated by Higgins I2 statistics, where an I2 value ≥ 50% was considered as high level of heterogeneity. Meta-regression analyses were performed to assess the associations between potential influencing indicators including smoking status, baseline diabetes status, baseline heart failure status, baseline cardiovascular disease events, baseline age, sex, baseline BMI, study duration, baseline SBP level, baseline DBP level, SBP changes between groups and DBP changes between groups.
To accommodate variations in BP reduction across trials, we further applied a standardization method as described in the systematic review and meta-analysis by Ettehad, Dena et al. [10]. This method adjusts the logarithm of each trial’s summary statistic (e.g. logHR) by multiplying it by 10/d, where d represents the mean SBP reduction in the trial. The logarithm of each trial’s summary statistic was adjusted (standardization) using the formula:
This standardization allows exhibiting results in terms of a uniform per 10 mmHg reduction in SBP or per 5 mmHg reduction in DBP. This approach ensures consistency in outcome interpretation across diverse trials.
To explore the relationship between the magnitude of BP reduction and the study outcomes, we implemented a dose-response meta-analysis utilizing the nonlinear fitting model by STATA 16.0 software. The ‘glst’ command was employed to analyse the effects across different dosage levels. The effect measurement (namely RR) for specific BP reduction values would be characterized as one-to-one correspondence manner with an algebraic analytic expression. The linear models would be employed when nonlinear relationships were not significant.
Publication bias was assessed by Egger’s test. Statistical significance was considered at p < 0.05. Statistical analyses were primarily performed by using the Review Manager statistical software package (version 5.3, Nordic Cochrane Centre, Copenhagen, Denmark) and the STATA statistical software package (version 16.0, Stata Corp, College Station, TX, USA).
Results
Study selection, study characteristics, and quality assessment
In total, 15 RCTs were included in this study, with 46719 participants in BP-lowering agent treatment group and 47763 participants in the control group. There were 1 trial investigating β-blockers, 8 trials investigating renin-angiotensin-aldosterone system inhibitors (RAAS-i), 4 trials investigating angiotensin receptor-neprilysin inhibitors (ARNI), and 2 trials investigating calcium channel blockers (CCB). The enrollment of the studies was shown in Figure 1. The baseline characteristics of each eligible RCT was summarized in Table S3. The risk of bias was evaluated by the Cochrane instrument and RoB2 tool, which suggested the low risk of bias arising from the randomization process, low risk of bias due to deviations from intended intervention, low risk of bias due to missing data, low risk in measurement of the outcome, and low risk in selection of the reported results for the included studies (Table S4 and Figure S1). The Egger’s test indicated no sign of publication bias (p = 0.693) (Figure S2).
Figure 1.
Flow diagram of included trials.
Standardized BP reduction and the risks of PAD
The standardized analysis revealed that each 10 mmHg reduction in SBP mediated by BP-lowering agents conferred a 37% increase in the risk of PAD in patients with cardiometabolic risk factors (RR = 1.37, 95% CI 1.08 to 1.74) (Figure 2). However, the standardized DBP reduction was not associated with the risk of PAD (RR = 1.26, 95% CI 0.94 to 1.69).
Figure 2.
Forest plots for standardized SBP reduction and the risk of PAD.
When stratified by the drug types of BP-lowering agents, the risk of PAD increased by 30% with each 10 mmHg SBP reduction in RAAS-i users (RR = 1.30, 95% CI 1.00 to 1.67), compared to non-users. However, the increased risk of PAD was not observed in patients using β-blockers, CCB or ARNI.
Meta-regression analyses
Meta-regression analyses suggested that more profound reduction difference in SBP between the intensive BP-lowering group and control group was associated with elevated risk of PAD (β = −0.111, 95%CI −0.219 to −0.002, p = 0.047) (Figure S3). Conversely, no significant associations between baseline BP, treated BP and the risk of PAD were revealed by meta-regression analyses (All P value > 0.05). Further analyses indicated that age, sex, baseline body weight, baseline BMI, pervious PAD history, percentage of diabetes mellitus, HF, hypertension or CVD did not modify the risk of PAD in patients receiving BP-lowering agents (All P value > 0.05).
Dose-response analysis
The linear fitting analysis indicated a linear association between SBP reduction and risk of PAD, with a 3.22% increase in risk for every 1 mmHg decrease in SBP (RR = 1.032, 95% CI 1.008 to 1.057, p = 0.009) (Figure 3). No significant nonlinear dose-response associations were observed between SBP reduction and PAD (p = 0.517).
Figure 3.
Dose-response analysis of SBP reduction and the risk of PAD.
However, the linear fitting analysis did not reveal any significant association between DBP reduction and the risk of PAD (RR = 1.040, 95% CI 0.995 to 1.087, p = 0.08) (Figure 3). The nonlinear analysis did not reveal a significant association between DBP reduction and its relationship with PAD (p = 0.200) either.
Discussion
Our study revealed that the magnitude of SBP reduction mediated by BP-lowering agents was associated with an increased risk of PAD in a dose-dependent manner. Each 10 mmHg reduction in SBP mediated by BP-lowering agents was shown to confer a moderately increased risk of PAD in patients with cardiometabolic risk factors. There was a linear association between SBP reduction and risk of PAD, with a 3.22% increase in the risk of PAD for every 1 mmHg reduction in SBP.
PAD is a clinical condition characterized by stenosis or blockage of the aorta or limb arteries. Chronic vascular endothelial injuries resulting from hypertension and smoking are often linked to the development of PAD. These injuries contribute to endothelial cell loss or dysfunction, which promotes a series of pathological processes that eventually result in thickening of the vascular wall, stenosis, and occlusion of the vascular lumen [11]. Hypertension often leads to an increase in arterial stiffness, a decrease in small artery caliber, and the formation of atherosclerotic plaques due to increased oxidative stress and inflammation [12,13].
The use of BP-lowering medications in patients with PAD has long been debated, with concerns that these drugs may worsen limb ischemia and interrupt the hemodynamic stability. On the basis of vascular stiffness and lumen stenosis, the decrease of limb perfusion may increase the risk of PAD [14]. Previous study observed a J-shaped curve relationship between the level of SBP and the risk of PAD events, with the lowest hazard ratio (HR) found in the 130–139 mmHg range. Both lower and higher SBP levels (below 130 mmHg and above 140 mmHg, respectively) were associated with increased risk of PAD events, with the highest risk observed in individuals with SBP less than 120 mmHg [6]. In our study, the proportion of participants with a baseline SBP of less than 130 mmHg was 15.54%, which increased to 32.45% after treatment. This led to an absolute increase of 16.91 percentage points. Similarly, the proportion of individuals with SBP less than 120 mmHg rose from 2.56% to 12.02%, corresponding to an absolute increase of 9.46 percentage points. These changes indicated that a larger proportion of participants achieved lower SBP targets after treatment. Therefore, the increase in the proportion of individuals with SBP below 130 mmHg, particularly those with SBP below 120 mmHg, might be the main source of the mild overall increased risk.
Notably, we found a robust linear dose-response association between SBP reduction and risk of PAD, with generally each 1 mmHg decrease in SBP associated with a 3.22% increase in the risk of PAD. This could be attributed to hypoperfusion resulting from excessive BP reduction, contributing to an elevated risk of PAD [14]. Hence, it is imperative to carefully regulate the magnitude of BP reduction to maintain a balance between treatment benefits and risks.
In all, the magnitude of BP reduction was associated with the risk of PAD. A reanalysis of ALLHAT data showed that adjusted HRs for a lower extremity PAD event were greatest with DBP <60 mmHg when referred to 70-79mmHg [15]. The INternational VErapamil-SR/Trandolapril (INVEST) study also reported heightened risk for low blood pressure in lower extremity hypertensive PAD patients [15]. These findings raised the concerns that intensive BP reduction strategies might increase the risk of PAD especially for the vulnerable patient with stiffened arteries and low peripheral artery perfusion [15]. ABI measurement should be employed as the preferred diagnostic tool for PAD monitoring, as it is a validated and non-invasive method widely recommended in clinical guidelines [16,17]. Rapid and profound BP reductions should be avoided, as they may increase the risk of PAD due to hypoperfusion. Instead, aiming for a gradual and moderate BP reduction to minimize the risk of PAD was recommended. In addition to the magnitude of BP reduction, BP variability has been shown to influence outcomes in patients with symptomatic PAD [18]. Maintaining BP stability is therefore crucial when implementing intensive BP control strategies. Furthermore, our findings align with recent recommendations on the individualized management of hypertension in PAD patients [19], which emphasize the importance of carefully balancing the cardiovascular benefits of BP reduction against the potential risks of PAD progression. Furthermore, previous study also indicated protective effects of certain BP lowering agents against PAD. The use of CCB could mitigate the progression of atherosclerosis [20]. A meta-analysis showed that CCB was associated with decreased risk of PAD compared with other antihypertensive agents or placebo [20]. In our study, the BP reduction mediated by CCB would not increase the risk of PAD. In this regard, CCB might be a favourable option for patients at risk of PAD requiring antihypertensive treatment.
In this study, we brought up new insights from a revisit to the old agenda of BP lowering and the risks of vasculopathy. Unlike traditional conditions as atherosclerosis, renal injuries or heart failure which gain exact benefits from BP lowering, intensive BP reduction was shown to be associated with an increased risk of PAD. Therefore, the traditional viewpoints holding that BP lowering would improve overall prognosis in patients with hypertension or other conditions requiring anti-hypertensive treatment might get challenged. The complexity of diseases as well as the pros and cons in corresponding treatments should be emphasized. Focusing on specific clinical conditions, balancing the risks and benefits in therapies, and clarifying the subject matter of each patient, would be substantial in satisfying the claim of precision medicine and treatment.
There are also some limitations in our study. Firstly, the PAD events analysed in this study were extracted from original publications or Clinicaltrials.gov adverse event reports. Although the definition of PAD might be more or less reflected by the ABI, the specific diagnostic criteria for PAD by ABI assessment were not uniformly provided in the original reports or Clinicaltrials.gov adverse event reports. Due to the lack of the relevant data, we were unable to provide the specific ABI diagnostic criteria for each included RCT. Further investigations are needed to validate our findings with uniform ABI diagnostic criteria. Secondly, since some of included studies did not take PAD events as their primary outcomes, the PAD events were extracted from the reports from the registered website, which might require further adjudications. Thirdly, due to the lack of information, we were unable to classify the PAD events as symptomatic or asymptomatic. Future studies are required to address this issue. Moreover, the population, study design, study duration, investigational agents vary among the included trials, from which the heterogeneity might rise. Therefore, we conducted sensitivity analyses and meta-regression analyses to deal with the heterogeneity and distinguish the potential confounders. In the future studies, by conducting special tests for PAD, such as ABI, maximal walking distance, and pain-free walking distance, clinicians may obtain more insightful information regarding the severity and functional impact of PAD.
Conclusion
In conclusion, compared with the control groups, intensive BP reductions mediated by BP lowering agents were associated with the risk of PAD in patients with cardiometabolic risk factors. Clinicians should carefully evaluate the risk-benefit balance of intensive BP reduction strategies and prioritize individualized BP management to mitigate the risk of PAD while pursuing cardiovascular benefits in patients with cardiometabolic risk factors. Monitoring should be recommended for the patients at high risk of PAD who receive intensive BP-lowering treatments. Further investigations are still needed to formulate optimal treatment strategies for the population at high risk of PAD.
Author’s contributions
Linong Ji, Xiaoling Cai, Chu Lin: Conceptualization, Methodology, Supervision, Project administration. Ruoyang Jiao, Zonglin Li, Xingyun Zhu: Formal analysis, Investigation, Visualization. Suiyuan Hu, Fang Lv, Wenjia Yang: Data curation, Investigation. Ruoyang Jiao, Zonglin Li: Writing - Original Draft. Chu Lin, Xiaoling Cai: Writing - Review & Editing. All authors contributed to the article and approved the submitted version.
Supplementary Material
Funding Statement
This work was supported by National Natural Science Foundation of China (No.81970698 and No.81970708) and Beijing Natural Science Foundation (No.7202216). The funding agencies had no roles in the study design, data collection or analysis, decision to publish or preparation of the manuscript.
Disclosure statement
LJ has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare. No other support from any organization for the submitted work other than that described above.
Registration
This study was registered in PROSPERO (CRD42021285866).
Data availability statement
All data supporting the findings of this study can be accessed in this manuscript and supplementary materials.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data supporting the findings of this study can be accessed in this manuscript and supplementary materials.