Effects of statin use on primary patency, mortality, and limb loss in patients undergoing lower-limb arterial angioplasty: a systematic review and meta-analysis

Peripheral arterial disease can progress to critical limb ischemia, which requires revascularization. The endovascular approach is associated with a lower long-term patency due to restenosis resulting from neointimal hyperplasia. Statins offer significant advantages in patients undergoing percutaneous interventions. However, there are few studies on statin therapy associated with improved clinical outcomes after endovascular treatment in this patients. This systematic review and meta-analysis examined the effects of statins (in comparison with no statin) on outcomes of lower-limb arterial angioplasty by evaluating patency, amputation and mortality. We searched MEDLINE, Academic Search Premier and CINAHL using a predetermined search strategy from inception to September 21, 2022. Study selection (first by title and abstract and then by full text) and data extraction was conducted by two independent reviewers. Risk of bias was assessed using the Newcastle-Ottawa Scale. According to data availability, we conducted meta-analysis using RevMan v.5.4. The search identified 841 relevant articles and included 10 studies with 43,543 patients. Statin use in patients before undergoing lower-limb arterial angioplasty was associated with improved primary patency at 12 (12.57%, 95% confidence interval [CI] 6.86–18.28, p < 0.0001) and 24 months (7.19%, 95% CI 1.02–13.37, p = 0.02), decreased mortality in 39% at 12 months (relative risk (RR): 0.61, 95% CI 0.55–0.74, p < 0.00001) and decreased limb loss in 23% in the studied patients (RR: 0.77, 95% CI 0.65–0.91, p = 0.003). Statin therapy before the procedure was associated with significantly improved patency and overall survival and decreased limb loss after lower-limb arterial angioplasty.


Impact statements
• Endovascular treatment of peripheral arterial disease has lower patency due to restenosis resulting from neointimal hyperplasia and statins offer significant advantages in patients undergoing percutaneous interventions. Statins stabilize the plaque, improve endothelial function, have anti-inflammatory and anti-thrombotic effects. • Pre-procedure statin improved primary patency, survival and limb salvage in patients undergoing lower-limb arterial angioplasty. • This study provides evidence to optimize the prescription of statins before the procedure in patients with peripheral arterial disease undergoing lower-limb arterial angioplasty.

Introduction
Peripheral arterial disease (PAD) affects about 200 million people worldwide and is primarily caused by atherosclerosis [1,2]. The prevalence of PAD rises with age and affects a substantial proportion of the elderly population (> 20% in > 80-year-old individuals). The rate for African-Americans is about twice that of non-Hispanic whites at any given age [1]. Other well-established risk factors for PAD include diabetes, hypertension, smoking, hyperlipidemia and advanced age [3]. Previous studies showed increased prevalence of PAD in men, but recent evidence demonstrates PAD is more common in women [4]. PAD can progress to critical limb ischemia, which is associated with a high rate of amputation and death [2]. The treatment of critical limb ischemia requires revascularization, and the endovascular approach is associated with a higher reduction in morbidity and mortality than vascular surgery [5]. Despite numerous advantages, the major drawback of endovascular interventions is the lower long-term patency, mainly due to restenosis resulting from postintervention neointimal hyperplasia [5][6][7].
Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol lowering, such as modulating inflammation, protecting the endothelium, and decreasing the coagulation cascade activity [8]. Moreover, statins exert several beneficial effects in patients with PAD, reduce the incidence of vascular events and improve claudication and walking distance [9]. Preoperative statin therapy reduces all-cause mortality in patients undergoing major non-cardiac vascular surgery and plays a beneficial role in the management of patients undergoing percutaneous renal artery revascularization, endovascular abdominal aortic aneurysm repair, carotid angioplasty/ stenting, and endovascular peripheral arterial interventions [10,11].
Statins offer significant short-and long-term advantages in patients undergoing percutaneous interventions. Besides reducing periprocedural mortality and morbidity, statins improve long-term outcomes and decrease the risk of clinical events in these patients [9]. Aiello et al. reported improved overall survival rates, primary and secondary patency, and limb salvage in patients receiving statins before angioplasty [12].

Aim
Statins exert several beneficial effects in patients with PAD and offer significant advantages in patients undergoing percutaneous interventions. However, there are few studies on statin therapy associated with improved clinical outcomes after endovascular treatment in patients with critical lowerlimb ischemia. Therefore, this systematic review and metaanalysis aimed to examine the effects of statins (in comparison with no statin) before lower-limb arterial angioplasty evaluating outcomes such as patency as well as the incidence of amputation and mortality.

Method
This systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (CRD42021227230) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [13]. The need for ethics approval to conduct this review was waived.

Search strategy and selection criteria
A systematic literature review was performed utilizing EBSCOhost to simultaneously search MEDLINE complete, Academic Search Premier and CINAHL with full text from inception from September 21, 2022. The groups of search keywords were: statin therapy OR statin use OR statins OR statin AND endovascular surgery OR endovascular therapy OR peripheral angioplasty OR lower extremity endovascular intervention OR lower-limb intervention OR endovascular OR endovascular procedures OR endovascular treatment OR angioplasty lower limb. There were no publication date restrictions applied.
After excluding duplicate articles, we screened the titles and abstracts of all unique references that were identified. Then, we retrieved and reviewed the full text of potentially relevant references. The search and study selection were conducted manually by two independent investigators (S.K.B. & D.W.J.). Disagreements were resolved via consensus with a third investigator (G.B.).
A study was included in this meta-analysis if it fulfilled four predefined criteria: (1) The study was designed as a randomized controlled trial (RCT) or prospective or retrospective observational analysis directly comparing statin versus no statin before lower-limb arterial angioplasty. (2) The study reported quantitative data on clinical outcomes of interest. (3) The study was published in English or Spanish any time to September 21, 2022. (4) The study did not include populations that were duplicates of those in other included studies in this meta-analysis to avoid counting the same patient twice. Studies not reporting primary or secondary outcomes of interest were excluded. When duplicates were identified, the most recent study was included unless the earliest version reported more relevant outcomes.

Data extraction and outcomes
Two reviewers independently extracted the relevant data from the eligible studies. All disagreements were resolved following discussion and a final decision was reached by consensus with a third reviewer. Data extracted included the name of the study, the name of the first author, year of publication, country of origin, number of patients in the study and in each group, inclusion and exclusion criteria, study design, baseline demographics, comorbidities, characteristic of the statin regimen, clinical presentation, procedure details, treated arteries, lesion type (occlusion or estenosis), TASC (Trans-Atlantic Inter-Society Consensus Document) classification, complications, patency or restenosis, limb loss or amputation and mortality.
The primary outcome was primary patency at 12 and 24 months. Primary patency was defined as the absence of restenosis, occlusion, or re-intervention in the treated arterial segment. Secondary outcomes were restenosis, mortality at 12 months and limb loss, as those were defined by the original studies.

Risk-of-bias assessment
Risk of bias was assessed independently by two investigators (S.K.B. & D.W.J.) using the Newcastle-Ottawa Scale [14]. The following domains for the cohort studies were evaluated: selection of participants, comparability, and measurement of outcomes. Discrepancies in quality assessment were resolved via consensus.

Statistical synthesis and analysis
Whenever possible, according to data identified in the literature, we conducted meta-analysis to summarize the results of the included studies, with inverse variance method for continuous and time-to-event outcomes and Mantel-Haenszel for binary outcomes. A random-effects model was used to account for heterogeneity among studies. Outcomes were analyzed and presented as hazard ratio (HR), relative risk (RR) or mean differences with the corresponding 95% confidence intervals (CIs). The I 2 statistic was used to evaluate for heterogeneity, and an I 2 > 75% was considered as indicating significant heterogeneity. Forest plots were used to graphically display the effect size in each study and the pooled estimates. A value of p < 0.05 was considered statistically significant. All analyses were performed using Review Manager (version 5.4).

Study selection and patient characteristics
The literature search yielded 733 potentially relevant records after duplicates were excluded. After screening titles and abstracts, 50 articles were retrieved for full-text evaluation; 10 studies satisfied the predetermined search criteria and were included in this meta-analysis as shown in the PRISMA flow diagram (Fig. 1) [13]. All included studies were retrospective cohorts and no RCTs were identified. Seven studies were conducted in the United States, one in Japan, one in Germany and one in Netherlands. The studies were assessed as having low risk of bias ( Table 1).
The included number of patients in each study ranged from 17 to 22,954 patients, and 60.98% of these were men. The mean patient age ranged from 49 to 77 years across the studies. Detailed patient characteristics and prevalence of comorbidities are presented in Table 2.
The majority of patients treated with peripheral angioplasty in the studies included in the systematic review had critical ischemia in the lower limbs. In a study by Kim et al. [20], patients with lesions in the femoropopliteal artery segments received endovascular treatment through the insertion of a nitinol stent; however, approximately 30% needed additional below-the-knee intervention, whereas in a study by Tomoi et al. [16], only patients with isolated below-theknee lesions were treated using endovascular interventions.  [17,21]. Not all publications described the technique used for angioplasty.
All patients used statins before lower-limb arterial angioplasty in the statin group. Statin treatment among the included studies is presented in Table 3.

Discussion
This was a systematic review and meta-analysis of the role of statin treatment before the lower-limb arterial angioplasty. Our results indicated that statin use was associated with improved primary patency at 12 and 24 months and decreased mortality at 12 months and limb loss in patients undergoing lower-limb arterial angioplasty.
The prevalence of PAD rises with age and affects a substantial proportion of the elderly population [1]. The studies included in this review are mostly in elderly patients [12,[15][16][17][18][19][20][21][22], except for Zil-E-Ali et al. study, in which the median age of the study group was 49 years (Mean: 49.3 ± 11.1) [23]. In addition, a higher proportion of male patients is also observed among the analyzed studies, despite recent evidence demonstrates PAD is more common in women [4]. However, women may be more asymptomatic or have atypical symptoms [4], which should explain gender-based disparities in PAD.
As in this meta-analysis, previous studies examining statin use before lower-limb arterial angioplasty showed that statins can improve primary patency 12 and 24 months after the intervention. The cumulative primary patency was  Zil-E-Ali et al. [23] **** ** * significantly higher at 12 and 24 months after endovascular intervention in the statin group [12]. Improved primary patency at twelve months associated with the use of statins was observed in patients who underwent femoropopliteal and infrapopliteal arterial angioplasty [15,19,20]. However, De Grijs et al. and Dosluoglu et al. found that statin use was not associated with improved primary patency in patients who received endovascular treatment [18,22]. In both studies, the statin group had more patients with diabetes, which may have influenced the results. Our study also found that statin use before lower-limb arterial angioplasty was associated with decreased mortality at 12 months after the intervention. Few studies have analyzed survival in patients following the use of statins and endovascular revascularization; however, most of these patients demonstrated decreased mortality [12,18,19,21].  [12] Atorvastatin (169), simvastatin (98), simvastatin + ezetimibe (12), lovastatin (22), and pravastatin (15) Before the procedure Kim et al. [20] Low-intensity statin therapy (9), moderate-intensity statin therapy (56), high-intensity statin therapy (26) − ACC/AHA 2013 Before the procedure Tomoi et al. [16] NA Before the procedure Hagenaars et al. [15] Simvastatin, 10 mg or 20 mg Before the procedure de Grijs et al. [22] Simvastatin (53), rosuvastatin (6), atorvastatin (45), pravastatin (8), lovastatin (17), and fluvastatin (2) Before the procedure Westin et al. [19] Simvastatin or atorvastatin (73%) Before the procedure Dosluoglu et al. [18] NA Before the procedure Zil-E-Ali et al. [23] NA Before the procedure Vogel et al. [17] Lovastatin, rosuvastatin, fluvastatin, Atorvastatin, pitavastatin, lovastatin, pravastatin, simvastatin, niacin + lovastatin, amlodipine + atorvastatin, niacin + simvastatin, ezetimibe + simvastatin More than 3 months before the procedure Stavroulakis et al. [21] NA Before the procedure Although statins are associated with improved patency and mortality after endovascular procedures, the role of secondary prevention in limb salvage has been reported with conflicting results, possibly due to different patient populations with divergent endpoints. Limb salvage rates were significantly higher in patients who were receiving preoperative therapy compared with those in the control [12,23,24]. Small trials have documented favorable vascular remodeling in patients taking statins, showing increases in femoral artery vessel distensibility and compliance [25]. However, other studies [16,18,19,26] found no association between statin therapy and limb salvage. Patients with severe arterial lesions and critical limb ischemia had worse rates of limb salvage in the cited studies, possibly owing to the severity of the presentation.
The mechanisms by which statins reduce clinical event rates following percutaneous coronary interventions and (possibly) other percutaneous revascularization procedures have not been fully elucidated [9]. Data derived from experimental and clinical trials provide several plausible hypotheses, including plaque stabilization (e.g. reduction of the number of inflammatory cells in atherosclerotic plaques, decreased secretion of matrix metalloproteinases, and inhibition of endogenous cholesterol synthesis in macrophages), increased nitric oxide synthesis, improvement of endothelial function, and reduction of platelet activation and adhesion. In addition, statins have been reported to exert important anti-inflammatory effects in vitro and in vivo as well as antithrombotic effects [9,[27][28][29]. The apoptosis of neointimal smooth muscle and subsequent reduction in intimal thickness and hyperplasia observed with statins may also contribute to the improved clinical results seen after endovascular intervention [30].
The period for which statin therapy should be initiated before the vascular intervention to achieve its beneficial effects is unknown. The use of statins should be started as soon as possible before an elective procedure. Ideally, statins should be initiated a minimum of 2 weeks prior to vascular surgery. In addition, patients should continue taking statins up to the evening before the open surgical or endovascular procedure [31].
Some limitations of the present analysis should be noted. First, only observational studies were included in this meta-analysis; therefore, statin treatment was not randomly assigned and was associated with other clinical characteristics that may have influenced the outcomes. Second, there was a lack of data for different statin types, dosages, adherence, and pretreatment duration across the included studies. Third, some studies did not indicate how the procedures were carried out nor did they present data about the localization and nature of the arterial lesions.

Conclusion
Statin therapy has been associated with improved outcomes in patients with PAD. Our meta-analysis found that statin therapy before ther procedure was associated with significantly improved patency and overall survival and decreased limb loss after lower-limb arterial angioplasty. More studies are required on patients who undergo endovascular procedures to elucidate specific benefits attributable to statins in limb-related outcomes as well as for defining the dose protocols and the appropriate period of use of the statin in relation to the time of arterial interventions.