Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia: Retrospective cohort study.

OBJECTIVES: Antiplatelet therapy following peripheral arterial endovascular intervention lacks high quality evidence to guide practice. The aim of this study was to assess the effect of three months of dual antiplatelet therapy on amputation-free survival following peripheral arterial endovascular intervention in patients with chronic limb threatening ischemia.
METHODS: A retrospective review of symptomatic patients undergoing primary peripheral arterial endovascular intervention over a seven-year period was performed. The primary outcome measure was amputation-free survival. A sample size calculation based on previous cohort studies suggested that 629 limbs would be required to show a difference between single and dual therapy. Kaplan-Meier estimates and multivariate logistic regression analysis of recorded baseline characteristics was performed to determine predictors of amputation-free survival. Dual antiplatelet therapy was routinely given for 3 months.
RESULTS: 754 limbs were treated with primary angioplasty and/or stenting over a 7-year period, 508 of these for chronic limb threatening ischemia. There was no difference in unadjusted amputation-free survival between patients with chronic limb threatening ischaemia taking single vs. dual antiplatelet therapy (69% vs. 74% respectively Log rank Chi2 = 0.1, p = .72). After adjusting for confounders, at 1 year there was also no significant difference in amputation-free survival between patients taking single vs. dual antiplatelet therapy [OR 0.8, 95% CI 0.5-1.2, p = .3]. There was no difference in rates of major bleeding between single and dual antiplatelet therapy.
CONCLUSIONS: There was no clear evidence of reduced amputation-free survival in patients with chronic limb threatening ischemia undergoing peripheral arterial endovascular intervention being treated with dual antiplatelet therapy for 3 months. This is at odds with other retrospective case series and highlights the limitations in basing clinical practice on such data. There is a need for an adequately powered, independent randomised trial to definitively answer the question.

Introduction

Antiplatelet therapy following peripheral arterial endovascular intervention lacks high-quality evidence to guide practice [1]. This is surprising given the large number of randomised trials to guide antiplatelet practice in other areas of treatment for peripheral arterial disease, and causes conflict between recommendations in guidelines [2,3]. It has also resulted in a variation in clinical practice between clinicians, centers and countries [4].

There is one small randomised trial examining single vs. dual antiplatelet therapy after endovascular intervention [5,6]. This lacked the power to compare clinically relevant outcomes such as amputation rates or amputation-free survival. The trial recruited forty patients in each arm and at 12 months there was no statistically significant difference between target lesion revascularisation in the dual antiplatelet arm (Aspirin and Clopidogrel) over Aspirin single therapy.

There is case-series evidence to support a benefit of dual antiplatelet therapy in patients undergoing peripheral endovascular intervention [7-9]. However, these series included a heterogenous patient mix including patients undergoing intervention for claudication and patients undergoing secondary intervention. The most important group of patients undergoing intervention for peripheral arterial disease are those with chronic limb threatening ischaemia who are at the highest risk of amputation or death if treatment fails [10]. This group is vastly under-represented in previous case series. Moreover, long (over 6 months) durations of antiplatelet therapy was used in these studies, however clinical practice varies worldwide and many UK units, including ours, used short (less than 6 months) courses [1,11].

The aim of this paper was to examine the clinically relevant differences between single and dual antiplatelet therapy following peripheral arterial intervention for chronic limb threatening ischaemia in a way which minimises previous case series’ flaws: a powered, clearly specified cohort with statistically valid follow up criteria and adjusted outcome reporting.

Methods

Study design

This was a retrospective cohort study of patients undergoing primary lower limb peripheral arterial endovascular intervention for claudication or chronic limb threatening ischaemia. The study was approved by the Aneurin Bevan University Health Board Research and Development department (ABUHB R&D reference number: SA/710/16) and registered on ANZCTR. The research and development approval waives the requirement for informed consent which is in place for all approved studies using the clinical workstation browser. The study is reported in line with the STROBE statement [12].

Study patients

Patients undergoing primary lower limb arterial endovascular intervention at the Royal Gwent Hospital, Newport between January 2010 and January 2017 were screened for inclusion. The Health Board’s electronic clinical workstation browser was used to collect anonymized data; all data were anonymized for collection and analysis. Clinical workstation is linked to the office for national statistics in the UK for mortality reporting.

Pre-procedural data associated with poor amputation-free survival [13,14] was collected on each patient including baseline blood tests (white cell count, haemoglobin, platelet count, urea, creatinine, eGFR and albumin), co-morbidities (ischaemic heart disease, diabetes, hypertension, congestive cardiac failure, chronic obstructive airways disease and cerebrovascular accident), smoking status, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker and statin usage. Data on anatomical location of the lesion and endovascular treatment device ((balloon—plain or drug eluting; stent—bare metal, drug eluting or covered) was also collected.

All patients were discussed by a multidisciplinary team before intervention. After discharge following intervention patients were routinely followed up at 6 weeks in an outpatient clinic. Patients with tissue loss were followed up in a wound healing service until the point of healing (defined as full epithelialization). Patients undergoing stent implantation were followed up with duplex surveillance at 3, 6, 9 and 12 months. Recurrent stenoses >75% were discussed by a multidisciplinary team and offered repeat intervention if clinically appropriate. The study end date was 30/09/2018, however, survival and re-intervention times were defined up to last known date of follow-up. The follow-up period was measured relative to the declared study end date. A follow-up index was calculated for each patient. This is defined as the ratio between the investigated follow-up period and the theoretically possible follow-up period to the pre-specified study end date [15]. The international classification of diseases was used for disease definitions, apart from ischaemic heart disease which includes angina and myocardial infarction definitions [16].

Primary (first) lower limb intervention for atherosclerotic peripheral arterial disease

Angioplasty or stenting with any device

Angioplasty or stenting of the distal infra-renal aorta with common iliac disease; common or external iliac arteries; superficial femoral artery; popliteal artery; tibio-peroneal trunk; anterior or posterior tibial artery; peroneal artery or any pedal artery.

Patients undergoing treatment for aneurysmal disease or for a complication of treatment of aneurysmal disease

Secondary or endovascular re-intervention to the same limb

Treatment proximal to the infra-renal aorta; mesenteric or renal vessels; upper limb or head and neck vessels

Hybrid revascularization procedures

Patients undergoing intra-arterial embolectomy, thrombectomy or thrombolysis, other than those where this was commenced immediately following primary angioplasty or stenting in order to treat a complication

Venous procedures (e.g. deep venous stenting)

Angioplasty or stenting of arterio-venous fistulas or arterio-venous malformations

Patients receiving therapeutic anticoagulation

Patients receiving dual antiplatelet therapy for another cause prior to peripheral endovascular intervention

Patients receiving no anti-platelet therapy at the time of discharge

Endpoints

Primary endpoint

Amputation-free survival (composite of mortality plus major lower limb amputation defined as above ankle) [2]. We have performed patient focus group work as part of the run up for a randomised trial of single vs. dual antiplatelet therapy which confirmed this to be the most important patient centered outcome after treatment for chronic limb threatening ischaemia. It is also a widely accepted effectiveness outcome in chronic limb threatening ischaemia used in several major randomised trials [2].

Primary safety endpoint

Major bleeding (using the International Society on Thrombosis and Haemostasis definition) [17].

Secondary endpoints

Survival, limb salvage, target lesion revascularisation, trends in dual antiplatelet therapy prescription with time.

Antiplatelet therapy

Antiplatelet therapy was prescribed by the consultant vascular surgeon or interventional radiologist looking after the patient. Choice of antiplatelet therapy was at the discretion of the attending surgeon/radiologist. There were no specific criteria for using single or dual antiplatelet therapy, it was dictated by the practice of the person performing the procedure. The hospital prescription would last for 4–6 weeks and a summary would be given to the patient and GP for continuation. Dual antiplatelet therapy was continued for a period of 3 months after intervention and long term single antiplatelet therapy was given after this.

Sample size calculation

In the previously published case series the rate of dual antiplatelet therapy varied: 31% in a Swedish registry study [7], 55% in a single centre study from America [8] and 69% in an American registry study [9]. The benefits of dual therapy also varied between the studies; with a hazard ratio [HR 0.54] in favour of dual antiplatelet therapy in the Armstrong et al single centre study, HR 0.89 for mortality in the American registry, and HR 0.72 and HR 0.77 for survival and amputation respectively in the Swedish registry. The variability in previous similar case series made it difficult to estimate the prevalence and treatment effect of dual therapy in our cohort a-priori.

Patients with chronic limb threatening ischaemia could not be analysed separately for a sample size calculation from the cohort studies above. Therefore a total sample size calculation was performed for all patients undergoing intervention presuming a similar case mix and the chronic limb threatening ischaemia patients were analysed alone in our study. Sample size calculations were based on a 40% prevalence of dual antiplatelet therapy and a hazard ratio 0.65 to estimate the treatment effect of dual therapy (our primary outcome is amputation-free survival) in our cohort. With mortality rates between 20%-30% and amputation rates 8%-15% in the previous three case series, the estimated event rate was 28%. Therefore, using standard size sample size calculation [18], we estimated that six hundred and twenty nine patients would be required to have 80% power to show a difference comparable to the published literature at the 5% level with a median follow-up of 36 months. Based on previous audit we knew that 120–140 procedures were performed annually, so on the assumption that we were likely to exclude approximately 25% of patients due to treatment of patients without chronic limb threatening ischaemia or who were on anticoagulation, we estimated that seven years (the period during which electronic records were available) should be enough to achieve adequate power to address the study question.

Statistical analysis

All data was anonymized prior to analysis. The data were cleaned by first resolving transcriptional discrepancies and clinical conflicts. Aberrant and extreme values were removed or transformed if the cause was inconsistent measurement units. All variables missing more than 15% of data were excluded from analyses. The sample median was substituted for missing continuous variables and the mode for missing categorical variables.

For descriptive data with a normal distribution the mean±standard deviation (SD) was specified and comparisons were performed using a two-sided student’s t-test. For data with non-normal distribution the median and interquartile range were given and comparisons made using the Mann Whitney U test. For categorical variables comparisons were performed using the Fisher’s exact test. Unadjusted event free survival was estimated using the Kaplan-Meier method and between group difference assessed using the log-rank test [19] Potential confounders of amputation-free survival were adjusted for: Baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and treating endovascular device (balloon—plain or drug eluting; stent—bare metal, drug eluting or covered). Confounder correction using Cox Proportional Hazards method was undertaken with stepwise selection of confounders through minimization of the Akaike Information Criterion to reduce model over-fitting. Scaled Schoenfeld residuals were analysed to assess for violation of the proportional hazards assumption [20].

The primary endpoint was also examined at 1-year post intervention as trials in cardiology suggest the greatest benefit to this time period [21], and to minimize error due to attrition. We used logistic regression analysis and odds ratios to analyze risk factors associated with poor amputation-free survival. Multivariate logistic regression was used to adjust for confounders (baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and treating endovascular device), with stepwise selection of significant confounding variables by minimizing the Akaike information criterion (AIC) [22]. A further sensitivity analysis was performed to assess the effect of drug eluting devices. Linear regression was carried out to examine trends of antiplatelet prescription with time. All statistical analysis was performed within the R statistical programming environment version 3.5.1 and for all tests a p value of < .05 was considered significant.

Results

Patient demographics and interventions

Nine hundred and twenty-seven patients were screened for inclusion in the study (Fig 1). Six hundred and twenty-five patients and seven hundred and fifty-four limbs met the inclusion/exclusion criteria were treated with primary angioplasty or stenting over the seven-year period. Five hundred and eight of these were performed in patients with chronic limb threatening ischaemia. The mean age of the entire cohort was 69.8±10.9 years; three hundred and ninety-six (63%) patients were male. The median follow-up time was 29 (8–33) months, with a mean follow-up index of 0.94±0.1. There were 244 deaths during the study period (208 patients with chronic limb threatening ischaemia and 36 with intermittent claudication). Only two variables were excluded because of >15% missing data: smoking and the Wound Ischaemia and Foot infection score.

Fig 1

Patient cohort development.

Amputation-free survival in patients with chronic limb threatening ischaemia

There were differences in single and dual therapy by anatomical location and endovascular treatment device used (Table 1).

Table 1

Baseline characteristics of patients with chronic limb threatening ischaemia.

	Single therapy n = 389		Dual Therapy n = 119	P
Aspirin (n)	318	Aspirin + Clopidogrel	113	-
Clopidogrel (n)	71	Aspirin + Prasugrel	5	-
		Aspirin + Ticagrelor	1	-
Concurrent statin n(%)	285(73)		92(77)	0.29
Concurrent ACEi n(%)	200(51)		59(50)	0.92
Co-morbidities
IHD n(%)*	173((44)		51(43)	0.92
Diabetes n(%)	222(57)		71(60)	0.53
Hypertension n(%)	303(78)		97(82)	0.26
CVE n(%)**	55(14)		25(21)	0.06
COPD n(%)	66(17)		22(18)	0.68
CCF n(%)	83(21)		30(25)	0.32
Blood results (Median(IQR))
Haemoglobin (g/L)	122 (109–138)		120 (108–136)	0.18
Platelets (109/L)	291 (236–365)		293 (229–364)	0.16
WCC (109/L)	9.4 (7.6–11.4)		9.4 (7.6–11.4)	0.27
Urea (mmol/L)	6.0 (4.4–8.1)		5.9 (4.4–8.3)	0.22
Creatinine (mmol/L)	79 (67–106)		79 (68–108)	0.94
eGFR	76 (57–98)		77 (56–99)	0.4
Albumin (g/L)	33 (28–37)		32 (27–36)	0.21
Minor amputations (n)	57		19	0.66
Major amputations
Transtibial (n)	45		9	0.24
Transfemoral (n)	25		6	0.6
Major bleeding events (n)	18		6	0.82
Anatomical location
Aorto-iliac	102		57	<0.00001
Femoro-popliteala	126		41	0.74
Below the kneeb	88		9	0.000245
Iliac + Fem-pop	6		1	1
Iliac + BTK	1		0	1
Fem-pop + BTK	65		11	0.06
Endovascular device
Balloon angioplasty	261		50	<0.00001
Drug eluting balloon	98		55	0.000012
Bare metal stent	5		2	0.67
Drug eluting stent	5		6	0.013951
Covered stent	1		4	0.003138

IHD = Ischaemic Heart Disease; CVE = Cerebrovascular Event; COPD = Chronic Obstructive Pulmonary Disease; CCF = Congestive Cardiac Failure; WCC = White Cell Count

* Ischaemic heart disease was defined as angina and/or previous myocardial infarction.

** CVE includes both stroke and transient ischaemic attack

a Femoro-popliteal (fem-pop) ends at the level of P2

b Below the knee (BTK) starts at P3

Overall unadjusted amputation-free survival for patients with chronic limb threatening ischaemia was 79% at 6 months, 71% at one year, 63% at 2 years and 55% at 3 years. There was no difference in unadjusted amputation-free survival (Log rank Chi2 = 0.1, p = .72 Fig 2).

Fig 2

Kaplan-Meir curve showing amputation-free survival for patients with chronic limb threatening ischaemia receiving single or dual antiplatelet therapy following peripheral endovascular intervention.

The Y axis shows probability of survival and the X axis shows time in months.

On adjusting for confounders (baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and endovascular device, S1 Table), amputation-free survival was not associated with choice of antiplatelet therapy [HR 0.94, 95% CI 0.7–1.3, p = .7].

The cardiology literature suggests benefit to one year from a course of dual antiplatelet therapy.11 When truncating follow-up at 1 year in this cohort there was also no significant difference in amputation-free survival between patients taking single or dual antiplatelet therapy [OR 0.8, 95% CI 0.5–1.2, p = .3] after adjusting for the following confounding variables: baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and endovascular device (S1 Table).

Major bleeding

There was no statistically significant difference in major bleeding between the dual antiplatelet therapy (n = 8) and single therapy group (n = 26) of patients (p = 1). There was no statistically significant difference in major bleeding between aspirin and clopidogrel in the single therapy group (21/437 patients taking aspirin vs 5/145 patients taking clopidogrel, p = 0.6). These trends were the same for chronic limb threatening ischaemia patients alone (p = .82).

Secondary endpoints in patients with chronic limb threatening ischaemia

Survival was no different between patients receiving single and dual antiplatelet therapy (Log Rank Chi2 = 0, p = .9). This was also the case after adjusting for confounders (baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin, angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and endovascular device, S1 Table; HR 1.0, 95% CI 0.7–1.4, p = .9).

There were eighty-five post intervention major lower limb amputations: 70 (17.6%) in the single therapy group and 15 (12.6%) in the dual therapy group. There was no difference in limb salvage rates between patients receiving single or dual antiplatelet therapy (Log Rank Chi2 = 1.7, p = .2). This was also the case after adjusting for confounders (baseline white cell count, haemoglobin, platelet count, urea, creatinine, eGFR, albumin, ischaemic heart disease, hypertension, diabetes mellitus, cerebrovascular event, congestive cardiac failure, chronic obstructive airways disease, statin and angiotensin converting enzyme inhibitor or angiotensin II receptor blocker usage, anatomical location of the lesion and endovascular device, S1 Table; HR 0.6, 95% CI 0.3–1.1, p = .1).

Target lesion revascularisation rates were no different between the groups. Re-intervention was performed in 152 (29%) limbs with 120 (31%) on single therapy and 32 (27%) on dual antiplatelet therapy post primary intervention (p = .5). The median time to reintervention was 6 (2–18) months.

A change in antiplatelet prescription was noted over time with clinicians prescribing clopidogrel rather than aspirin single therapy and dual antiplatelet therapy more frequently with time (Fig 3). There was an increasing trend in the proportion of patients being discharged on dual antiplatelet therapy increased from 2% in 2010 to 26% in 2016 (p = .0003).

Fig 3

Change in antiplatelet prescribing post peripheral endovascular intervention over time.

Dual antiplatelet therapy (R2 = 0.94, p = .0003) Clopidogrel (R2 = 0.41, p = .12). Y axis shows number of cases and X axis shows year of prescription.

Discussion

There was no statistically significant difference in amputation-free survival or major bleeding events between patients on single or dual antiplatelet therapy after lower limb endovascular intervention for chronic limb threatening ischaemia.

The main finding is interesting for a number of reasons. Although the study had appropriate statistical power to detect differences similar to the previously published literature, the case mix is different with fewer diabetics in our study than one of the large cohort studies used for the calculation [7]. As event rates were higher in the diabetic cohort in this study it may be no effect is shown in our data as a result. There were difference in use of single and dual therapy by both anatomical location and endovascular device used. This is in keeping with a previous international survey of practice [4] and would potentially confound previous unadjusted studies.

Three months of dual therapy was used in our cohort as opposed to longer courses in previous cohorts [8,9]. In trials comparing the duration of dual antiplatelet therapy after percutaneous coronary intervention there are debates over the optimal length of treatment because of the balance of risk and benefit [11]. Durations of antiplatelet therapy longer than twelve months after percutaneous coronary stenting cause harm as a result of increased major bleeding rates which means most guidelines do not recommend courses over six to twelve months [23-26]. Conversely, the STOPDAPT-2 study showed benefit for only a 1 month course of dual therapy [27]. As this is undefined following percutaneous lower limb intervention it may be the case that six or twelve months rather than three months of dual therapy would show a difference between the groups at one year.

Major bleeding events showed no difference between the groups. The overall rate of major bleeding was 54 per 1000 patients which is similar to that reported in previous randomised trials [1]. The sample size in this study is therefore too small to detect a significant difference, but it is reassuring that there is no large discrepancy.

The trend in increasing use of dual therapy over time is in keeping with previous work showing this to be the case [4]. It may be that clinical practice is being extrapolated from cardiology or from randomised trials of newer technologies such as drug eluting stents, where dual therapy was often specified in the protocol with no justification [28]. Either way there is a potential that this causes more harm than good while we do not fully understand the benefit for amputation-free survival.

This analysis has a number of limitations. Retrospective studies are limited by the type and quality of the data collected. Even though a sample size calculation was performed this is not as powerful for retrospective data as if the study was prospective. It is helpful to guide the number of patients included in the study but cannot be seen as definitive. There is still the possibility of type 2 error in any of the comparison, especially as the groups become smaller. Smoking status is associated with increasing atherosclerotic burden as well as increased risk of major adverse cardiovascular events [29]. There was lack of sufficient data on the smoking status of patients in this cohort so we were unable to account for the effect of confounding due to this factor in our analysis. A lack of strict antiplatelet protocol means that longer or shorter durations may have been taken by patients and no compliance checks were made.

The study also has several major strengths for a retrospective cohort. A sample size calculation was performed based on previous publications in this area and there was sufficient statistical power to detect differences similar to those seen in previous published studies. We focused on patient centered clinical endpoints in patients with chronic limb threatening ischaemia, who benefit most from these interventions. Inclusion/exclusion and endpoint criteria were prespecified and adhered to and follow-up reporting was robust, as demonstrated by the mean follow-up index of 0.94.

This research alone is not high enough quality to make recommendations for practice, nor is any other cohort study or previously published randomized trial in the area [5-9]. The conflicting results make it clear that an adequately powered randomised trial in this area is required to make practice recommendations.

Conclusion

There was no evidence of improved amputation-free survival in patients with chronic limb threatening ischaemia undergoing peripheral arterial endovascular intervention being treated with 3 months of dual antiplatelet therapy over those on a single agent. This is at odds with other retrospective case series and highlights the dangers in basing clinical practice on such data. There is a need for a high-quality randomised trial to definitively answer the question of whether dual antiplatelet therapy is of benefit after peripheral endovascular intervention.

Multivariate analysis with confounder correction.

(DOCX)

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24 Mar 2020

PONE-D-20-04980

Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia: retrospective cohort study

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Reviewer #1: General comments: The authors present a case controlled study on the possible association between DAPT and AFS. I have several comments outlined below.

1. I wonder what the reason was to study AFS as your primary endpoint because this would reduce the “power” of your study when looking at isolated limb outcomes. Please justify.

2. Line 47: Please provide also unadjusted results, in the form of Kaplan Meier/log rank testing, with rates overtime, i.e. at one year.

3. Line 49: it is unclear what this OR refers to re: intervention vs comparator. Is single antiplatelet better?

4. Line 91: I wonder if case-control studies can have power calculated, as you mention at this point. To the best of my knowledge, power is estimated only for RCTs.

5. Line 105: please add country.

6. Line 181 Sample size calculation: please refer to my previous comment.

7. Table 1: please include percentages for categorical data. Also provide exact p values, not just <0.05.

8. Line 309: please present results of univariate analysis,

9. Line 328: please check your statistics because I am not aware of a Chi2=0.

10. Line 336: the difference between the groups “70 (17.6%) in the single therapy group and 15 (12.6%)” could had been significant if your sample size was bigger, i.e. a type II error. Please comment.

Reviewer #2: Excellent article very well written. A retrospective observational study tracking >500 patients undergoing endovascular intervention.

Very tightly controlled design with robust analysis and good understanding of limitations of study design.

Couple of minor points - figures 2 and 3 have come across poorly. Figure 3 needs more description of the y axis - I assume this is cases?

Information from the STOPDAPT-2 study would be beneficial as this suggests that only 1 month of DAPT is required in DEB/DES in cardiac PCI. This may improve reader acceptance of this study.

Additionally, it is clear that in this study only approximately 1/3 of Drug eluting devices led to DAPT, which appears slightly unusual.

Was there any correlation between anatomical location and drug eluting status? This may be an interaction between covariates which may be of interest. I am sure this has been considered however.

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Reviewer #1: Yes: Stavros Kakkos

Reviewer #2: No

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Submitted filename: PLOS DAP review.docx

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1 May 2020

* all page numbers refer to the tracked changes manuscript

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Response: The formatting has been checked and updated.

2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Response: Thank you, this has been added.

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"This study was supported by the NIHR Biomedical Research Centre at

432 University Hospitals Bristol NHS Foundation Trust and the University of

433 Bristol. The views expressed in this publication are those of the authors and

434 not necessarily those of the NHS, the National Institute for Health Research or

435 the Department of Health and Social Care. GKA was supported by a Royal

436 College of Surgeons Research Fellowship. CPT was supported by Learning

437 and Research at North Bristol NHS trust.".

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Response: Thanks, the funding information in acknowledgments has now been moved to the correct place.

Reviewer #1: General comments: The authors present a case controlled study on the possible association between DAPT and AFS. I have several comments outlined below.

1. I wonder what the reason was to study AFS as your primary endpoint because this would reduce the “power” of your study when looking at isolated limb outcomes. Please justify.

Response: There was some information on AFS choice in the primary endpoint section of the methods which has now been expanded. This now reads (line 172 page 9), “Primary endpoint: Amputation-free survival (composite of mortality plus major lower limb amputation defined as above ankle).2 We have performed patient focus group work as part of the run up for a randomised trial of single vs. dual antiplatelet therapy which confirmed this to be the most important patient centered outcome after treatment for chronic limb threatening ischaemia. It is also and is a widely accepted effectiveness outcome in chronic limb threatening ischaemia used in several major randomised trials.2”

2. Line 47: Please provide also unadjusted results, in the form of Kaplan Meier/log rank testing, with rates overtime, i.e. at one year.

Response: Thanks, this has been added.

3. Line 49: it is unclear what this OR refers to re: intervention vs comparator. Is single antiplatelet better?

Response: This has also been clarified by rewording the section to: “There was no difference in unadjusted amputation-free survival between patients with chronic limb threatening ischaemia taking single vs. dual antiplatelet therapy (69% vs. 74% respectively Log rank Chi2=0.1, p= .72). After adjusting for confounders, at 1 year there was also no significant difference in amputation-free survival between patients taking single vs. dual antiplatelet therapy [OR 0.8, 95% CI 0.5-1.2, p= .3].”

4. Line 91: I wonder if case-control studies can have power calculated, as you mention at this point. To the best of my knowledge, power is estimated only for RCTs.

Response: It is valid to do so, but is obviously nowhere near as powerful as for prospective studies. There are various arguments about different ways to do (for example here: Johnston KM, Lakzadeh P, Donato BMK, Szabo SM. Methods of sample size calculation in descriptive retrospective burden of illness studies. BMC Med Res Methodol. 2019;19(1):9. Published 2019 Jan 9. doi:10.1186/s12874-018-0657-9), it but we chose a ‘standard’ RCT type approach. This has been added to the discussion page 22 line 567, “Even though a sample size calculation was performed this is not as powerful for retrospective data as if the study was prospective. It is helpful to guide the number of patients included in the study but cannot be seen as definitive.”

5. Line 105: please add country.

Response: Thanks, this has been added.

6. Line 181 Sample size calculation: please refer to my previous comment.

Response: Thanks, as above.

7. Table 1: please include percentages for categorical data. Also provide exact p values, not just <0.05.

Response: This has been added.

8. Line 309: please present results of univariate analysis,

Response: We didn’t run univariate analyses, just a multivariate model. We have now added the full model as a supplementary table (S1).

9. Line 328: please check your statistics because I am not aware of a Chi2=0.

Response: The Chi2 can equal zero when the expected values are equal to the observed values.

10. Line 336: the difference between the groups “70 (17.6%) in the single therapy group and 15 (12.6%)” could had been significant if your sample size was bigger, i.e. a type II error. Please comment.

Response: Thanks, this should already have been commented on in the discussion. It has been added to the text page 22 line 567, “There is still the possibility of type 2 error in any of the comparison, especially as the groups become smaller.”

Reviewer #2: Excellent article very well written. A retrospective observational study tracking >500 patients undergoing endovascular intervention.

Very tightly controlled design with robust analysis and good understanding of limitations of study design.

Couple of minor points - figures 2 and 3 have come across poorly. Figure 3 needs more description of the y axis - I assume this is cases?

Response: Thanks, this was actually completely missing from 3. We’ve added an axis description to the title of each figure.

Information from the STOPDAPT-2 study would be beneficial as this suggests that only 1 month of DAPT is required in DEB/DES in cardiac PCI. This may improve reader acceptance of this study.

Response: STOPDAPT-2 as been added to the discussion page 21 line 543.

Additionally, it is clear that in this study only approximately 1/3 of Drug eluting devices led to DAPT, which appears slightly unusual.

Response: Yes, it wasn’t routinely used. This was also shown as common in our international survey of practice (reference 4)

Was there any correlation between anatomical location and drug eluting status? This may be an interaction between covariates which may be of interest. I am sure this has been considered however.

Response: This was not considered because it will exist by definition: DES are only routinely available for the SFA. It would also be off topic.

Reviewer 3

An interesting and timely manuscript. I have a number of comments.

1. Any study looking at PAD patients is difficult and results tempered by the heterogeneity seen within the population – especially as the authors have included aorto-iliac / femoropopliteal and infrapopliteal endovascular revasculairsation in this dataset. Decision making around the role of antiplatelet therapy can be nuanced and often involves lesion type / endovascular result / run off / patient risk of bleeding – especially given a lack of antiplatelet therapy protocol within the department. To this end such data would be useful to allow further interpretation of the results. Specifically, eg TASC lesion criteria treated, run off – CFA / SFA / PFA disease of AI treatment and crural run off for FP treated lesions. Of more importance is risk of bleeding for an older and frail patient group as this may well have influenced decision making eg use of PPI / H2 antagonists at the time of revascularisation as a proxy for GI bleed risk or a HASBLEED 2 score. I am also surprised that allergy to aspirin / other antiplatelet therapies wasn’t an exclusion criterion.

Response: Thanks, these are included in table 1 to the best extent available to us. We don’t have power to stratify results by TASC/anatomical location etc so doing so would be meaningless. Allergy would have been an exclusion by definition as it is a retrospective study and these patients were taking aspirin.

2. The authors admit that there is in built bias with regard to decision making around dual antiplatelet therapy – was there a difference between surgeons and radiologists. While managing the change in antiplatelet strategy is straightforward if the patient is an in patient what was the logistical arrangement for those patient attending as an out patient. Was the patient sent home with a prescription or was this left in the hands of the GP with a discharge letter – this is important as planned antiplatelet management does not equate to initiation of therapy / adherence. Adherence is a whole different ball game which this study would not be able to determine and has to be accepted as a weakness of the study.

Response: This information has been added to the methods page 10 line 245, “The hospital prescription would last for 4-6 weeks and a summary would be given to the patient and GP for continuation.” Adherence/compliance was listed as a limitation in the discussion.

3. The trend of change in AP prescription does cloud the data and it may be that the use of DAP is better but this hasn’t been seen yet as the effect are seen out to 2 o r3 or 4 years. Could the authors comment on this.

Response: The latest patients were included in 2016 so that we had at least 2 years of follow up (median 29 months). If benefit hasn’t already been seen it would not be seen after this.

4. There are a number of assumptions around the sample size calculation which need to be mentioned in the discussion.

Response: We used standard SSC methodology. It was based on other retrospective data, but often so is a SSC for a major RCT. If good data were available for a SSC the study would be pointless!

5. It is not well signposted in the manuscript that claudicants were excluded. Further is the data looking at per limb or per patient. Did the fact that a patient had two limbs treated alter the management of antiplatelet regime. Eg. If the ipisilateral limb was treated and patient put on DAP, and the the contra limb treated – was this patient then excluded as they were already on dual antiplatelet therapy? If the same patient was initially on a single AP agent and then after the second procedure put on DAP in which group were they classed? Would the data be cleaner if only those patients having one limb treated were included.

Response: The title does state that we are interested in CLTI. It is also stated in each of the results subsection headings.

Contra limb; in the CLTI group there were all separate patients as well as limbs, i.e. there were no patients counted twice. To clarify this we have made several edits to the results.

6. The authors need to define the comorbidities – ie. What is actually meant by ischaemic heart disease – by having detailed patients notes I am sure that they have strict definitions for inclusion.

Response: Thanks, we have added this information to the methods page 8 line 188.

7. Which variables were excluded with data missing of >15%. Which of the variable used had significant data missing eg>5%?

Response: This has been added to the results page 14 line 353, “Only two variables were excluded because of >15% missing data: smoking and the Wound Ischaemia and Foot infection score.” It was already listed as a limitation in the discussion.

22 May 2020

Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia: retrospective cohort study

PONE-D-20-04980R1

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This has made an improvement on an already sturdy paper.

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Reviewer #2: No

1 Jun 2020

PONE-D-20-04980R1

Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia: retrospective cohort study

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