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

doi:10.21203/rs.3.rs-1714306/v1

Purpose

This study aimed to determine whether the administration of statins before, during or after lower-limb arterial angioplasty was associated with improved primary patency, mortality, and limb loss through a meta-analysis.

Methods

All studies on statin administration in patients undergoing lower-limb arterial angioplasty that reported the outcomes of interest (primary patency, mortality and limb loss) were included in a meta-analysis.

Results

Nine studies were included in this meta-analysis. Statin use in patients 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 improved amputation-free survival (AFS) in 35% (Hazard ratio: 0.65, 95% CI: 0.46–0.793, p = 0.0198). However, statin use was not associated with decreased limb loss among patients in the included studies (RR: 0.76, 95% CI: 0.56–1.04, p = 0.08).

Conclusion

Statin therapy was associated with significantly improved patency, overall survival, and AFS but not with limb loss after lower-limb arterial angioplasty.

peripheral arterial disease

lower-limb arterial angioplasty

statin

primary patency

mortality

limb loss

Peripheral arterial disease (PAD) affects about 200 million people worldwide and is primarily caused by atherosclerosis [1, 2]. 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 [3]. Despite numerous advantages, the major drawback of endovascular interventions is the lower long-term patency, mainly due to restenosis resulting from postintervention neointimal hyperplasia [3, 4, 5].

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 [6]. Moreover, statins exert several beneficial effects in patients with PAD, reduce the incidence of vascular events and improve claudication and walking distance [7]. 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 [8, 9].

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 [7]. Aiello et al. reported improved overall survival rates, primary and secondary patency, and limb salvage in patients receiving statins before angioplasty [10].

However, there are few studies on statin therapy associated with improved clinical outcomes after endovascular treatment in patients with critical lower-limb ischemia. Therefore, this systematic review and meta-analysis aimed to examine the effects of statins on outcomes of lower-limb arterial angioplasty by evaluating patency as well as the incidence of amputation and mortality.

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 [11]. The need for ethics approval to conduct this review was waived.

Search strategy and selection criteria

Systematic searches were conducted in Medline (via PubMed), Scopus and Scielo. The search strategy used in all databases was: statin and endovascular surgery OR statin and endovascular therapy OR statin and peripheral angioplasty OR statin and endovascular peripheral arterial intervention OR statin and lower extremity endovascular intervention OR statin and lower-limb intervention OR statin and endovascular. The references of the included studies were also manually reviewed to identify other eligible articles.

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 by two independent investigators. Disagreements were resolved via consensus with a third investigator.

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, during, or after 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 from January 1, 2000 to November 21, 2020. 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, mortality, and amputation-free survival (AFS).

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, limb loss, and AFS, as those were defined by the original studies.

Risk-of-bias assessment

Risk of bias was assessed by two investigators using the Newcastle–Ottawa Scale [12]. 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, we conducted a meta-analysis to summarize the results of the included studies. A random-effects model was used to account for heterogeneity among studies. Outcomes were analyzed and presented as Hazard ratios (HR), relative risk (RR), or mean differences and the corresponding 95% confidence intervals (CIs). Higgins I² statistic was used to account for heterogeneity, and an I² > 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) and R (version 4.1.0), package meta (version 4.18-1).

Study selection and patient characteristics

The literature search yielded 727 potentially relevant records after duplicates were excluded. After screening titles and abstracts, 44 articles were retrieved for full-text evaluation; 9 studies satisfied the predetermined search criteria and were included in this meta-analysis as shown in the PRISMA flow diagram (Fig. 1) [11]. All included studies were retrospective cohorts and no RCTs were identified. Six 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 (Supplementary Table 1).

The included number of patients in each study ranged from 17 to 22954 patients, and 49.7% of these were men. The mean patient age ranged from 69 to 77 years across the studies. Detailed patient characteristics and prevalence of comorbidities are presented in Table 1.

Table 1

Baseline characteristics of patients in the included studies
Study	Country	Total patients N	Statins/no statins N	Mean Age (years)	Men (%)	HNT (%)	DM (%)	DYS (%)	CKD (%)	SMK (%)
Aiello 2012 De Grijs 2018 Vogel 2013 Kim 2016 Westin 2014 Tomoi 2013 Stavroulakis 2017 Dosluoglu 2014 Hagenaars 2000	USA USA USA USA USA Japan Germany USA Netherlands	646 250 22954 135 380 812 816 717 17	319/327 131/119 11.619/11.335 91/44 246/134 169/643 445/371 397/320 6/11	77 76 76 72 69 76 74 69 72	52.5 45 46 65 56 69 65 99 52	84 90 69 96 85 73 NA 74 29	69.5 46 38 61 61 70 46 47 41	NA 51 NA 72 NA 51 NA 70 NA	36 16 19 13 NA 63 42 NA NA	10.2 39 NA 72 67 36 NA NA 58
Continuous data are presented as the means; categorical data are given as the counts (percentage)
Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; DYS, dyslipidemia; HTN, hypertension; NA, not available; SMK, smoker (current/former)

The majority of patients treated with peripheral angioplasty in the studies included in the meta-analysis had critical ischemia in the lower limbs. In a study by Kim et al. [13], 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. [14], only patients with isolated below-the-knee lesions were treated using endovascular interventions. In contrast, in studies by Hagenaars et al. and De Grijs et al., only patients with lesions in the femoropopliteal artery segments received endovascular the cumulative treatment [15, 16]. Aiello et al., Westin et al., and Dosluoglu et al. reported treating artery lesions in different arterial segments [10, 17–18], and Vogel et al. and Stavroulakis et al. did not describe the treated arterial segments [19, 20]. 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 2.

Table 2

Characteristics of the statin regimens
Study	Statin used (number of patients)	Time of statin use in relation to the procedure
Aiello et al., 2012 [10]	Atorvastatin (169), simvastatin (98), simvastatin + ezetimibe (12), lovastatin (22), and pravastatin (15)	Before the procedure
Kim et al., 2016 [13]	Low-intensity statin therapy (9), moderate-intensity statin therapy (56), high-intensity statin therapy (26) − ACC/AHA 2013	Before the procedure
Tomoi et al., 2013 [14]	NR	Before the procedure
Hagenaars et al., 2000 [15]	Simvastatin, 10 mg or 20 mg	Before the procedure
de Grijs et al., 2018 [16]	Simvastatin (53), rosuvastatin (6), atorvastatin (45), pravastatin (8), lovastatin (17), and fluvastatin (2)	Before the procedure
Westin et al., 2014 [17]	Simvastatin or atorvastatin (73%)	Before the procedure
Dosluoglu et al., 2014 [18]	NR	Before the procedure
Vogel et al., 2013 [19]	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., 2017 [20]	NR	Before the procedure
NR = not reported.

Primary patency, mortality, limb loss, and AFS

Our pooled analysis showed that statin use was associated with improved primary patency at 12 (12.57, 95% CI: 6.86–18.28, p < 0.0001) and 24 months (7.19, 95% CI: 1.02–13.37, p = 0.02) after the angioplasty (Figs. 2a and 2b). There was a decrease of 39% in mortality at 12 months (RR: 0.61, 95% CI: 0.55–0.74, p < 0.00001; Fig. 3). However, statin use was not associated with decreased limb loss in the studied patients (RR: 0.76, 95% CI: 0.56–1.04, p = 0.08; Fig. 4). Moreover, there was an increase of 35% in AFS (HR: 0.65, 95% CI: 0.46–0.793, p = 0.0198; Fig. 5).

This was a systematic review and meta-analysis of the role of statin treatment in patients undergoing 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 but not with limb loss in patients undergoing lower-limb arterial angioplasty. Moreover, statin use was associated with improved AFS.

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 significantly higher at 12 and 24 months after endovascular intervention in the statin group in the study by Aiello et al., wherein over 60% of the treated arterial lesions were femoropopliteal and multilevel arterial stenosis and 66% of the arterial lesions were classified as TASC C or D lesions [10]. Improved primary patency at twelve months associated with the use of statins was observed in patients who underwent femoropopliteal and infrapopliteal arterial angioplasty [13, 17]. Simvastatin therapy limits lumen reduction at 12-month follow-up after angioplasty for femoropopliteal artery disease [15]. However, Dosluoglu et al. and De Grijs et al. found that statin use was not associated with improved primary patency in patients who received endovascular treatment [16, 18]. In a study by De Grijs et al. all patients undergoing primary nitinol stenting of the femoral and popliteal arteries and the statin group had significantly higher rates of diabetes and chronic kidney disease [16]. Dosluoglu et al., in a study with 717 patients (99% men), treated patients with critical ischemia exclusively, and the statin group had more patients with diabetes, which may have influenced the results [18].

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 [10, 17, 18, 20].

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.

In a study with 646 patients, Aiello et al. demonstrated that limb salvage rates were significantly higher in patients receiving preoperative therapy than those in the control group (at 12 months after intervention, 87% vs. 71%, p < 0.05), despite the higher number of patients with diabetes in the statin group [10]. This outcome may be attributed to the inclusion of patients who had femoropopliteal (over 35%) and multilevel arterial lesions (over 20%) [10]. Moreover, Todoran et al. stated that statin use prior to the performance of the index procedure was associated with a lower risk of amputation during the follow-up of patients undergoing percutaneous revascularization of the superficial femoral artery (HR 0.11, 95% CI 0.2–0.6, p = 0.010) [21]. Small trials have documented favorable vascular remodeling in patients taking statins, showing increases in femoral artery vessel distensibility and compliance [22]. In addition, in a study on about 22000 patients, Vogel et al. indicated that patients who underwent endovascular surgery and used preoperative statins were less likely to have an amputation at 12 months after angioplasty compared with those who did not, for patients with the diagnosis of claudication. However, this association was not observed in patients with rest pain and ulceration/gangrene. Some considerations need to be made about this study, because the patients with claudication were younger and used statins more frequently than the other groups. Several comorbid diseases were unequally distributed across the study population; increased PAD severity was associated with an increased proportion of patients with diabetes mellitus or renal failure [19].

A benefit from using statins in limb salvage was also observed when this medication was initiated after revascularization in patients with PAD. Peters et al. demonstrated that new statin users with critical limb ischemia had a lower risk of major amputation than non-users (HR 0.73, 95% CI 0.58–0.93). The probability of major amputation was 2.9% lower in the chronic limb-threatening ischemia group [23].

However, Fernandez et al. reviewed predictors of outcomes after endovascular tibial artery interventions in patients with critical limb ischemia and found no association between statin therapy and limb salvage or wound healing [24]. A study by Tomoi et al. demonstrated that statin treatment before successful endovascular treatment for isolated below-the-knee arterial lesions with critical limb ischemia does not influence limb salvage [14]. However, this study included only below-the-knee arteries in patients with critical limb ischemia (76.7% with tissue loss), the majority having arterial lesions classified as TASC D and occlusion of the three leg vessels, which demonstrates the severity of the disease and can explain the absence of beneficial effects of statins in terms of this outcome [14]. Of the 812 patients included in the study, only 169 were using statins, which may have limited the results. Moreover, there were more patients with diabetes in the statin group. Further, Dosluoglu et al. stated that statin use was not associated with improved 5-year limb salvage rates in patients who underwent endovascular treatments [18]. This study focused on different arterial territories in the patients with critical limb ischemia and reported a greater prevalence of patients with diabetes in the statin group [18]. Westin et al. demonstrated that the amputation rate did not significantly differ between the control patients and those using statins, even with improved patency in the infrapopliteal segment; however, a trend favoring statin use was observed. Patients prescribed statin medications had higher rates of diabetes mellitus and multilevel stenosis, and only patients with critical ischemia were treated in this study [17]. Patients with critical limb ischemia had worse rates of limb salvage in the cited studies, possibly owing to the severity of the presentation.

Few studies have reported improvements in the AFS with statin use. The risk of death and major amputation (AFS) was significantly decreased in patients who received treatment with statins [17, 20], particularly in ambulatory patients [14].

The mechanisms by which statins reduce clinical event rates following percutaneous coronary interventions and (possibly) other percutaneous revascularization procedures have not been fully elucidated [7]. 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 anti-thrombotic effects [7, 25, 26, 27]. 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 [28].

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 [29].

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.

Statin therapy has been associated with improved outcomes in patients with PAD. Our meta-analysis found that statin therapy was associated with significantly improved patency, overall survival, and AFS but not with 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.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Conceived and designed the analysis: SKB; JBTR.

Data collection: SKB; DW; GB

Contributed data/analysis tools: SKB, JBTR

Performed the analysis: SKB

Wrote the paper: SKB; DW; GB

Ethics approval

The need for ethics approval to conduct this review was waived.

Consent to participate

Not applicable

Consent to publish

Not applicable

Data availability

Not applicable

Acknowledgements

Not applicable

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SupplementarydataSTEBAB2CPL51MI5.docx

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

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Materials And Methods

Search strategy and selection criteria

Data extraction and outcomes

Risk-of-bias assessment

Statistical synthesis and analysis

Results

Study selection and patient characteristics

Primary patency, mortality, limb loss, and AFS

Discussion

Conclusion

Declarations

References

Supplementary Files

Status:

Version 1