Impact of antihypertensive treatment on cardiovascular event reduction in patients with asymptomatic carotid artery stenosis: a systematic review and meta-analysis

¹Department of Internal Medicine, Marshfield Clinic, Wisconsin, United States of America, ²Department of Rheumatology, Marshfield Clinic, Wisconsin, United States of America, ³Marshfield Clinic, Wisconsin, United States of America, ⁴Department of Cardiology, Marshfield Clinic, Wisconsin, United States of America

^&Corresponding author
Apurva Popat, Department of Internal Medicine, Marshfield Clinic, Wisconsin, United States of America

Introduction    

Globally, cardiovascular disorders remain a leading cause of morbidity and mortality, with particular significance in patients with vascular disease [1]. These events encompass a spectrum of acute and chronic manifestations, including myocardial infarction, stroke, transient ischemic attacks, and cardiovascular death [2,3]. The prevention of such events has become increasingly important in modern medical practice, especially among those with pre-existing vascular conditions [4]. The duration and intensity of blood pressure management have emerged as critical factors in determining cardiovascular outcomes, and prompt early intervention may provide superior long-term benefits [5].

Asymptomatic carotid artery stenosis (CAS) is attributed to the narrowing of carotid arteries without overt neurological symptoms [6,7]. Despite its asymptomatic nature, it serves as a major risk factor for other cardiovascular events and stroke [8,9]. The pathological difference between asymptomatic and symptomatic CAS is mainly associated with stability and plaque morphology. Asymptomatic CAS demonstrates low inflammatory activity with a thicker fibrous cap showing more stable plaques and leading to a lower risk of immediate rupture, but consistent vascular burden for a long period. In contrast, symptomatic CAS involves more rupture-prone unstable plaques, demonstrating large lipid core, thin fibrous cap, and increased cell infiltration due to inflammation, which contributes to embolism and acute ischemic events [8-11]. CAS involves complex interactions between hemodynamic forces, inflammatory processes, and vascular remodeling influenced by different antihypertensive agents [10,11]. The association between CAS severity and cardiovascular risk is continuous, with greater degrees of stenosis associated with higher event rates [12].

Antihypertensive medications are essential in cardiovascular disease management, encompassing several major drug classes with distinct mechanisms of action [10,13,14]. Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors target the renin-angiotensin-aldosterone system, with agents such as telmisartan, valsartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, and eprosartan demonstrating significant efficacy in blood pressure management [15,16]. Whereas, calcium channel blockers (CCBs), including nifedipine, felodipine, amlodipine, isradipine, diltiazem, clevidipine, nicardipine, and verapamil modulate the influx of calcium in vascular smooth muscle cells, causing vasodilation and reduced peripheral resistance [17]. In addition, beta-blockers consisting of metoprolol, carvedilol, atenolol, propranolol, nebivolol, bisoprolol, labetalol, esmolol, nadolol, timolol, pindolol, and sotalol, reduce cardiac workload through sympathetic nervous system inhibition [18]. Thiazide diuretics, including hydrochlorothiazide, chlorthalidone, indapamide, metolazone, and bendroflumethiazide, decrease blood volume through enhanced sodium excretion [19].

Hence, the current study is performed to comprehensively explore the impact of antihypertensive treatment in asymptomatic CAS patients for the reduction of cardiovascular events by assessing the effectiveness of various classes of antihypertensive medications in this population, with particular consideration of their effects on carotid plaque progression and stability, and to understand their impacts on different outcomes of cardiovascular disease, including myocardial infarction, stroke, and cardiovascular death.

Methods     

The current review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [20].

Identification and selection of studies: a comprehensive literature search was conducted from inception to 2024 on the Web of Science, Cochrane Library, Cumulative Index for Nursing and Allied Health Literature (CINAHL), PubMed, and Medline databases.

Search strategy: the keywords used with medical subject headings (MeSH) terms in different combinations to optimize the search consisted of: “antihypertensive treatment”, or “angiotensin II receptor blockers”, or “irbesartan”, or “valsartan”, or “losartan”, or “candesartan”, or “eprosartan”, or “olmesartan”, or “azilsartan”, or “telmisartan”, or “calcium channel blocker”, or “amlodipine”, or “nifedipine”, or “felodipine”, or “nicardipine”, or “isradipine”, or “clevidipine”, or “verapamil”, or “diltiazem”, or “atenolol”, or “beta blockers”, or “metoprolol”, or “bisoprolol”, or “propranolol”, or “carvedilol”, or “nebivolol”, or “labetalol”, or “esmolol”, or “nadolol”, or “timolol”, or “pindolol”, or “sotalol”, or “thiazide diuretics”, or “hydrochlorothiazide”, or “chlorthalidone”, or “indapamide”, or “metolazone”, or “bendroflumethiazide”, and “carotid artery stenosis”, or “carotid artery constriction”, or “carotid artery narrowing”, or “carotid artery occlusion”, or “carotid artery obstruction”, or “reduced lumen of the carotid artery”, or “carotid atherosclerosis with stenosis”, or “chronic carotid artery disease”.

Study selection: for inclusion in the study, the articles were screened and selected by two reviewers independently. The conflicts among the reviewers were resolved collaboratively or through discussion with the third reviewer. The retrieved results were exported to Zotero screening software, which automatically detected retracted articles. In addition, it identified duplicate records, which a reviewer manually merged. The reviewers then screened the remaining articles.

Eligibility criteria: this systematic review included research related to the impact of antihypertensive therapy on cardiovascular event reduction in patients with asymptomatic CAS that was published from inception to 2024, described in the English language with full-text availability. The articles were selected based on the modified population, intervention, comparison, primary outcomes, and study design (PICOS) criteria [21]. The PICOS criteria in the present review were described as P: patients with asymptomatic CAS, I: antihypertensive therapy, C: various antihypertensive therapies, O: cardiovascular event reduction, and S: observational cohort studies or randomized controlled trials (RCTs). Whereas, the exclusion criteria consisted of articles not related to the context, non-availability of full-text, and not described in English. Moreover, letters, opinion pieces, editorials, conference abstracts, study protocols, reviews, and meta-analyses were also excluded.

Methodological quality assessment: for methodological quality assessment of the RCTs, the risk of bias visualization (robvis) tool was used [22,23]. Additionally, to evaluate the risk of bias (ROB) for cohort studies, the Newcastle-Ottawa Scale (NOS) was utilized [24].

Data selection and extraction: data sets consisting of authors, study settings, and designs, and population characteristics (size, age, intervention type, primary outcomes, secondary outcomes, objectives, and findings) were systematically extracted from the included studies and tabulated using Microsoft Excel 2019.

Data analysis: the extracted data were analyzed according to the focused outcome measures. For meta-analysis, Review Manager software version 5.4.1 (RevMan, Cochrane Collaboration) was used to pool quantitative data from included studies. Standardized mean differences (SMD) were calculated for continuous outcomes (e.g., rCBF for ACE inhibitors and BP for calcium channel blockers) with 95% confidence intervals (CI) to assess the effect of antihypertensive interventions. The SMD was chosen as the effect measure to account for variations in measurement scales across studies. A random-effects model was applied due to anticipated clinical and methodological heterogeneity, such as differences in patient populations, intervention durations, and study designs. Heterogeneity was assessed using the I² statistic and chi-squared test, with I² values >50% indicating substantial heterogeneity, prompting exploration of potential sources. Forest plots were generated in RevMan to visualize pooled SMDs, CIs, and p-values, with the software´s ‘inverse variance´ method used for pooling continuous data.

Sensitivity analyses were conducted to evaluate the robustness of results by excluding studies with a high risk of bias or those with shorter follow-up periods, as identified during quality assessment. No subgroup analyses were performed due to the limited number of studies and insufficient data on patient subgroups (e.g., by age, sex, or stenosis severity), though such analyses are recommended for future research. Publication bias was not formally assessed due to the small number of studies included (fewer than 10), as per Cochrane recommendations, but funnel plots were visually inspected in RevMan where feasible to detect potential reporting bias. Missing data were addressed by excluding studies with incomplete outcome reporting from the meta-analysis. All statistical tests were two-sided, with a significance threshold of p < 0.05.

Results     

Study selection: initially, from the overall 540 records, 187 duplicate records were eliminated. Additionally, two ineligible records were retracted by the automation tools. Furthermore, 302 records were excluded following the screening of the titles and abstracts of the studies. Of the remaining 49 articles identified for retrieval, one study could not be accessed. Following this, for eligibility, 48 articles were assessed, after which 39 articles were excluded due to patients with non-asymptomatic CAS, non-availability of articles in the English language, and articles not investigating cardiovascular events. Finally, three cohort studies and six RCTs that fulfilled the criteria were incorporated [25-33]. The selection strategy for studies according to the PRISMA flow diagram is illustrated below (Figure 1).

Methodological quality assessment: the cohort studies showed a favorable methodological quality (Annex 1). In addition, the included RCTs demonstrated an overall low ROB (Figure 2).

Data selection and extraction: this review included RCTs and observational studies investigating the effects of antihypertensive medications on carotid vascular health across different regions, including Armenia, Denmark, Spain, the USA, Sweden, and Italy. Moreover, the study population included patients with asymptomatic CAS. The studies explored various antihypertensive medications that involved ARBs, CCBs, beta-blockers, and specific medications like isradipine, enalapril, valsartan, and candesartan (Table 1). In addition, the studies examined outcomes including carotid vascular resistance, intima-media thickness, blood pressure management, carotid plaque progression, and cerebrovascular effects (Table 2, Table 3).

Meta-analysis inhibitor treatment outcomes of Angiotensin-converting enzyme (ACE): ACE inhibitors are essential in decreasing the incidence of cardiovascular events in asymptomatic CAS. Enalapril improved the carotid hemodynamic profile without inducing any significant harmful effect on cerebral blood flow (CBF) [28]. In addition, enalapril consistently lowered systemic BP with enhancement of regional carotid circulation. However, inter-individual variability in carotid remodeling responses ranged from minimal disease regression to significant progression.

Additionally, fosinopril lowered BP and retarded the carotid atherosclerosis process, an important marker for stroke risk [30]. There was significantly less CC-IMT progression in patients treated with fosinopril compared to hydrochlorothiazide (HCTZ)-treated subjects, demonstrating the dual action of ACE inhibitors in managing both the hemodynamic and structural components of carotid artery disease. Similarly, administration of enalapril led to a measurable decline in systolic and diastolic BP [25]. In one patient with left internal carotid artery occlusion (LICO), a decrease in BP from 140/79 mm Hg to 128/78 mm Hg was observed after enalapril administration, reflecting the efficacy of ACE inhibitors for hypertension management.

Enalapril and ramipril intervention was found to be particularly safe and effective in the case of CAS. Patel et al. (1996) found that a single dose of 5 mg of the enalapril and ramipril agents did not alter regional CBF significantly, showing their safety in hypertensive patients with CAS of high grade. This is important in minimizing the risk of cerebral hypoperfusion while effectively controlling systemic hypertension [31]. Moreover, according to Chang et al. (2013), ACE inhibitors decreased stroke events and cardiovascular deaths in asymptomatic CAS, consequently supporting the outcomes [27].

For meta-analysis (Figure 3), statistical data from two included studies were used to assess the effectiveness of enalapril on regional CBF (rCBF) in elderly asymptomatic CAS patients [28,31]. The pooled analysis favored the experimental group with standardized mean differences (SMD = 2.62, 95% CI: -0.84, 6.08), though results were statistically insignificant (P = 0.14) and show high heterogeneity (I² = 94%).

Calcium channel blockers (CCBs) treatment: CCBs reduced cardiovascular events and improved vascular hemodynamics among patients with asymptomatic CAS, in which isradipine enhanced carotid hemodynamics without altering rCBF. According to Akopov and Simonian (1997), isradipine reduced systolic and diastolic BP while simultaneously enhancing blood flow in CAS [28]. The vascular resistance in the ipsilateral carotid artery was reduced through vasodilation caused by isradipine. Moreover, there were no severe cerebral perfusion impairments in patients with chronic or recent hypertension and unilateral internal CAS [28].

Additionally, lacidipine, a dihydropyridine CCB, reduced vascular remodeling and improved cerebral perfusion. Lacidipine led to a significant reduction in BP (from 165 ± 21/91 ± 8 to 154 ± 12/86 ± 12 mmHg) and carotid intima-media thickness (IMT) [29]. In addition, lacidipine protected cerebral perfusion, maintaining adequate blood flow in patients with CAS, unlike HCTZ.

Furthermore, over 36 months, amlodipine slowed the progression of carotid artery atherosclerosis [32] as in the amlodipine group, a decrease of 0.0126 mm IMT was observed (P=0.007), whereas the placebo group exhibited a 0.033 mm increase. Compared to non-CCB-based regimens, amlodipine-based regimens demonstrated a 10% reduction in the risk of overall cardiovascular events (OR: 0.90; 95% CI: 0.82-0.99; P=0.02) and total mortality (OR: 0.95; 95% CI: 0.91-0.99; P=0.01). Furthermore, amlodipine showed superior protection against stroke compared to other antihypertensive drugs (OR: 0.84; 95% CI: 0.79-0.90; P<0.00001) [32].

To assess the effect of CCBs (isradipine and lacidipine) on BP for meta-analysis, statistical data from two included studies were used (Figure 4). The study by Akopov and Simonian (1997) analyzed the effects of isradipine [28] while Semplicini et al. (2000) investigated lacidipine intervention [29]. The pooled estimate favored the experimental group, with an SMD of 2.20 (95% CI: -3.25 to 7.64), though the results were statistically insignificant (P=0.43).

Thiazide diuretic treatment: according to Zanchetti et al. (2004), HCTZ reduced BP (from 167 ± 16/95 ± 5 to 162 ± 24/90 ± 14 mmHg), which is crucial in mitigating the progression of atherosclerosis in asymptomatic CAS. Despite this reduction, HCTZ reported less efficacy in comparison to fosinopril for slowing the progression of carotid IMT, a key marker of atherosclerosis [30]. This highlighted that while HCTZ contributes to cardiovascular risk reduction through blood pressure management, it may not provide additional vascular protective effects beyond its antihypertensive action.

Similarly, Semplicini et al. (2000) compared HCTZ versus lacidipine on cerebral perfusion in a study population with hypertension and CAS. The findings revealed that HCTZ effectively reduced BP but was associated with a slight decline in CBF (from 167 ± 16/95 ± 5 to 162 ± 24/90 ± 14 mmHg), suggesting a potential risk for impaired cerebral perfusion in this patient population [29]. These findings demonstrate the need for balancing antihypertensive efficacy against the preservation of cerebral hemodynamics during the use of thiazide diuretics in patients with CAS.

Angiotensin receptor blockers (ARBs) treatment: ARBs reduce cardiovascular events by improving vascular health, reducing the risk of stroke, and significantly decreasing the hazard ratio for patients [27]. These agents controlled hypertension and comorbid conditions strongly associated with increased cardiovascular event risks, such as chronic kidney disease and coronary artery disease. The patients on ARB therapy reported a low incidence of stroke in comparison to the patients who were not on the same treatment, further reiterating ARBs' role in effective risk management [27]. In addition, the annual and 5-year stroke rates were 0.7% and 3.5% respectively, for ARB treatment. This shows that ARBs perform an essential function in lowering the risk of transient ischemic attacks and stroke by stabilizing BP and reducing vascular inflammation [27].

Beta-blocker treatment: labetalol effectively reduced mean arterial pressure (from 100 mmHg to 80 mmHg; p < 0.01) in hypertensive episodes post-carotid endarterectomy. In contrast, contralateral Vmean remained unaffected by labetalol, emphasizing the drug's targeted impact on the ipsilateral side affected by hyperperfusion [26]. In addition, metoprolol CR/XL demonstrated significant effects on plaque characteristics and cardiovascular outcomes over time. Plaques in participants treated with metoprolol for 36 months were significantly more echogenic compared with the untreated ones (57.3 ± 16.8 vs. 51.8 ± 20.0, p = 0.006, respectively) [33]. Additionally, over an 8-year follow-up, active treatment with beta-blockers reduced cardiovascular event rates by 17% versus 37% for placebo (p = 0.011), highlighting the greater benefit in individuals with pre-existing atherosclerosis [33].

Discussion     

The review investigated the impact of antihypertensive medications in asymptomatic CAS patients for reducing cardiovascular events through direct blood pressure management, plaque stabilization, and vascular remodeling. Among patients with asymptomatic CAS, significant variations were observed in the effectiveness of different antihypertensive drug categories. ACE inhibitors, particularly enalapril and fosinopril, demonstrated dual benefits by effectively lowering BP while simultaneously improving carotid hemodynamics [28,30,31]. The meta-analysis, though statistically insignificant, suggested a positive trend favoring enalapril's effect on rCBF [28,31]. CCBs like isradipine and lacidipine improved carotid hemodynamics without compromising cerebral perfusion [28,29]. Amlodipine reduced both inflammation markers and macrophage infiltration when combined with atorvastatin, leading to a 10% reduction in overall cardiovascular events [32]. However, one of the major aspects of interpreting the results from primary investigations is the impact of concomitant interventions, mainly involving statins [32]. The patient populations receiving statins along with antihypertensive medications may have contributed to improvements in cardiovascular health, as there is no isolation effect of antihypertensive intervention observed from that of concurrent lipid-lowering treatment, making blood pressure management challenging. Hence, future research should focus on independent treatments (lipid-lowering agents versus antihypertensive intervention) in enhancing cardiovascular outcomes.

Thiazide diuretics, while effective in BP reduction, showed limitations in protecting against atherosclerosis progression compared to other drug classes. HCTZ successfully reduced BP but was associated with potential risks of impaired cerebral perfusion [29,30]. ARBs demonstrated significant effectiveness in stroke prevention, with studies showing a remarkable reduction in 5-year stroke rates in treated patients.

Beta-blockers like labetalol were effective in managing post-carotid endarterectomy hypertension and cerebral hyperperfusion symptoms [26], as metoprolol CR/XL significantly improved plaque echogenicity over 36 months and demonstrated a substantial reduction in cardiovascular event rates (17% versus 37% in placebo) over an 8-year follow-up period [33]. This finding can be utilized for clinical purposes, mainly as risk stratification for asymptomatic CAS, as increased echogenicity reflects more stable plaques. Hence, beta-blockers can be used as an adjunct in stabilizing plaques along with their antihypertensive effects, as echogenicity improvements serve as a surrogate marker. The combination therapy approach, particularly with statins, showed enhanced benefits across multiple outcomes, suggesting the importance of comprehensive treatment strategies in managing CAS.

The differential effectiveness of antihypertensive medications can be attributed to their distinct mechanisms of action and their effects beyond blood pressure management. ACE inhibitors' dual benefit likely stems from their ability to modulate the renin-angiotensin system, which affects both BP and vascular remodelling [34]. This favorable effect on carotid hemodynamics without the impairment of CBF may show that such drugs execute a delicate equilibrium between systemic BP reduction and local vascular wall function.

The better performance of CCBs to maintain cerebral perfusion with a reduction in BP may be related to their direct vasodilatory effects on the cerebral vasculature [35,36]. Increased efficacy of combination therapy with statins suggests a synergistic action through both hemodynamic and inflammatory pathways in atherosclerosis [37]. The limited efficacy of thiazide diuretics in preventing the progression of atherosclerosis despite good blood pressure management would suggest that a reduction in BP alone is not sufficient for optimal vascular protection.

The benefit of ARBs on stroke rates implies that, apart from their antihypertensive properties, the stabilization of plaques and vascular inflammation reduction due to this class of drugs occurs along with the aforementioned mechanism. Beta-blockers control post-endarterectomy complications and temporal improvement of plaque characteristics. The limited efficacy of thiazide diuretics in preventing the progression of atherosclerosis, despite blood pressure management, underscores the need for targeting multiple pathways in vascular disease. The reduction in stroke rates with modern medical management, particularly with ARBs, represents a significant improvement over historical data from studies involving asymptomatic CAS, highlighting the evolution of treatment strategies. The findings regarding beta-blockers' effects on plaque characteristics provide new evidence supporting their use in specific clinical scenarios, expanding upon previous knowledge of their cardiovascular benefits.

Strengths and limitations: this review comprehensively evaluated multiple classes of drugs, providing a wide-ranging understanding of their effects. In addition, it presents an elaborate evaluation of several cardiovascular outcomes, offering key aspects related to the impact of antihypertensive treatments. However, the heterogeneity in the design of the studies and their various measures of outcome limits the general applicability of the results. In addition, the limited availability of a long-term follow-up might pose a challenge for assessing the sustained effect of interventions. Moreover, the review focused on and included studies published in the English language, limiting the recruitment of key information from the studies published in other languages.

Furthermore, the review highlighted the need for individualized selection of antihypertensive therapy, depending on the severity of stenosis and a wide range of patient characteristics. Treatments considered by clinicians should take into account not only BP-lowering efficacy but also plaque-stabilizing properties. The findings also emphasized the use of comprehensive cardiovascular risk assessment in treatment decisions and underscores the importance of follow-up monitoring of the progression of CAS in treated patients. Additionally, future studies should investigate cardiovascular outcomes over the long-term follow-up period, optimal targets of BP concerning the various severities of stenosis, and combination therapies. In addition, further studies should be carried out on personalized treatment approaches according to the molecular and imaging markers of plaque vulnerability.

Conclusion     

The review provides valuable insights related to the impact of antihypertensive treatments in asymptomatic CAS patients for reducing cardiovascular events. Managing cardiovascular events is complex, and different antihypertensive treatments have different mechanisms of action, with varying efficacies in stabilizing carotid plaques and reducing cardiovascular events. ACE inhibitors and CCBs demonstrate superior outcomes in providing both blood pressure management and vascular protection, though with varying levels of statistical significance. Additionally, the effectiveness of combination therapy, especially with statins, highlights the importance of multi-modal treatment approaches. Moreover, beta-blockers effectively managed post-surgical complications and improved plaque characteristics. This highlights the evolution and complexity of managing asymptomatic CAS with antihypertensive therapy. Hence, the differential effects of antihypertensive treatments on vascular health, cerebral perfusion, and long-term outcomes emphasize the significance of personalized treatment approaches.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Conception and study design: Apurva Popat, Gauri Pethe, Sweta Yadav, Srinivasulu Sathipati, and Param Sharma. Database search: Apurva Popat, Gauri Pethe, and Sweta Yadav. Data collection, data analysis, data interpretation, manuscript drafting and manuscript revision: Apurva Popat, Gauri Pethe, Sweta Yadav, Srinivasulu Sathipati, and Param Sharma. Guarantor of the study: Apurva Popat. All the authors read and approved the final version of this manuscript.

Tables and figures     

Table 1: demographic and population characteristics of the studies reporting overall condition and intervention types

Table 2: characteristics of the included observational studies reporting the impact of antihypertensive treatment in asymptomatic carotid artery stenosis

Table 3: characteristics of the included randomized controlled trials reporting the impact of antihypertensive treatment in asymptomatic carotid artery stenosis

Figure 1: study selection strategy

Figure 2: traffic lights plot the Robvis assessment results

Figure 3: forest plot of standardized mean differences between experimental and control groups across two studies on the effect of enalapril on rCBF

Figure 4: forest plot of standardized mean differences comparing experimental and control groups across two studies on the effect of CCBs on blood pressure

Annex     

Annex 1: quality assessment results of the cohort studies using the Newcastle-Ottawa scale (PDF - 156KB)

References