Screening for Peripheral Artery Disease Using the Ankle-Brachial Index: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Abstract

Importance:

Peripheral artery disease (PAD) is associated with a high risk for cardiovascular events and poor ambulatory function even in the absence of symptoms. Screening for PAD with the ankle-brachial index (ABI) may identify patients in need of treatment to improve health outcomes.

Objective:

To systematically review evidence for the US Preventive Services Task Force on PAD screening with the ABI, the diagnostic accuracy of the test, and the benefits and harms of treatment of screen-detected PAD.

Data Sources:

MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant English-language studies published between January 2012 and May 2, 2017. Surveillance continued through February 7, 2018.

Study Selection:

Studies of unselected or generally asymptomatic adults with no known cardiovascular disease.

Data Extraction and Synthesis:

Independent critical appraisal and data abstraction by 2 reviewers.

Main Outcomes and Measures:

Cardiovascular morbidity; PAD morbidity; mortality; health-related quality of life; diagnostic accuracy; and serious adverse events.

Results:

Five studies including 5,864 participants were included that examined the indirect evidence for the benefits and harms of screening and treatment of screen-detected PAD. No population-based screening trials evaluated the direct benefits or harms of PAD screening with the ABI alone. A single diagnostic accuracy study of the ABI compared to magnetic resonance angiography gold-standard imaging found low sensitivity (7–34%) and high specificity (96–100%) in a screening population. Two adequately powered trials (n=4,626) in asymptomatic populations with and without diabetes with a variably defined low ABI (≤0.95 or ≤0.99) showed no statistically significant effect of aspirin 100 mg daily for composite CVD outcomes (adjusted hazard ratio [HR] 1.00 [95% CI, 0.81–1.23] and HR 0.98 [95% CI, 0.76–1.26]). One trial (n=3,350) demonstrated a nonstatistically significant increase in major bleeding events with the use of aspirin (HR 1.71 [95% CI, 0.99– 2.97]) and no statistically significant increase in major gastrointestinal bleeding (RR 1.13 [95% CI, 0.44–2.91]). Two exercise trials (n=932) in screen-relevant populations reported no differences in quality of life, Walking Impairment Questionnaire walking distance, or symptoms at 12 and 52 weeks; no harms were reported.

Conclusions and Relevance:

There was no direct evidence and limited indirect evidence on the benefits of PAD screening with the ABI in unselected or asymptomatic populations. Available studies suggest low sensitivity and lack of beneficial effect on health outcomes, but these studies have important limitations.

Peripheral artery disease (PAD) is associated with a high risk for cardiovascular (CVD) events and poor ambulatory function.^1,2 Because it is often asymptomatic, PAD is underdiagnosed, and as a result, those who have it may not receive appropriate treatment.^3,4 Early detection and treatment of PAD could improve health outcomes by initiating: (1) risk factor modification in people with undiagnosed atherosclerosis to reduce CVD outcomes and (2) interventions to slow functional decline of the lower-extremity.

The most commonly used screening test for PAD is the ankle-brachial index (ABI), which is the ratio of the ankle and brachial systolic blood pressures. While the ABI is recommended in patients with symptoms,⁵ less is known about the benefits and harms of its use for early detection and treatment in asymptomatic patients. In 2013, the United States Preventive Services Task Force (USPSTF) concluded that evidence was insufficient (I statement) to assess the balance of benefits and harms of screening for PAD and CVD risk assessment with the ABI in asymptomatic adults.⁶

The aim of this systematic review was to update the evidence on the benefits and harms of screening for PAD using the ABI, including the diagnostic accuracy of the test, and the benefits and harms of treating screen-detected patients, to inform the USPSTF in updating its recommendations. The USPSTF used this review, accompanied by a companion review on the utility of ABI for CVD risk prediction,⁷ to update its previous recommendation.

METHODS

Scope of Review

This review addressed 5 key questions (KQs), shown in Figure 1. Additional methodological details, including a detailed description of study selection and a list of excluded studies, and additional tabular outcome data for exercise trials are available in the full evidence report at https://www.ncbi.nlm.nih.gov/books/NBK526319/

Figure 1.

Analytic Framework²⁶

Abbreviations: ABI = ankle brachial index; PAD = peripheral artery disease

Data Sources and Searches

This review is an update of the screening, diagnostic accuracy, treatment, and harms KQs of a prior systematic review commissioned by the USPSTF.⁸ All previously included studies were reviewed for potential inclusion and Ovid Medline, PubMed, and the Cochrane Central Register of Controlled Trials were searched to identify new literature published between January 2012 and May 2, 2017 (eMethods in the Supplement). Additionally, recent systematic review reference lists were examined^9–17 and ClinicalTrials.gov was searched to identify relevant ongoing trials. Since May 2, 2017, ongoing surveillance through article alerts and targeted searches of journals with a high impact factor and journals relevant to the topic was conducted to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted on February 7, 2018 and identified one screening trial that was formally evaluated for inclusion but did not meet the review’s criteria.

Study Selection

Two reviewers independently reviewed 4,194 unique citations and 105 full-text articles against a priori inclusion criteria (Figure 2 and eTable 1). This review focused on screen-detected or generally asymptomatic adults without known CVD; therefore, studies whose participants primarily had the classic PAD symptom of intermittent claudication were excluded. This review allowed studies with participants reporting atypical symptoms with higher baseline values for ABI and lower extremity function who might also be representative of a screen-detected group.³ For each KQ, analyses were specified a priori for the following population characteristics: age, sex, race/ethnicity, smoking history, and presence of diabetes or hypertension. These are presented where available but were rarely reported. The credibility of subpopulation analyses was evaluated based on the timing of planned analyses, interaction testing for heterogeneity of treatment effect, baseline comparability, and control for confounders.¹⁸

Figure 2.

Literature Search Flow Diagram

Legend: Jan, January; Sep, September

^a Reasons for exclusion:

Aim: Study aim was not relevant

Setting: Study was not conducted in a country relevant to US practice, or was conducted or recruited from hospital or specialty settings such as vascular clinics or laboratories that typically represented populations selected for known or highly suspected PAD

Population: Study was not conducted in unselected or community-dwelling generally asymptomatic adults (KQs 1–3) or study was not conducted in screen-detected or generally asymptomatic adults with PAD or abnormal ABI (KQs 4 and 5)

Outcomes: Study did not report required outcomes

Intervention: Intervention was out of scope

Design: Study did not use an included design

Does not use reference standard: For KQ 2 and KQ 3, the ABI was not compared to an eligible reference standard

Quality: Study was poor quality

The primary outcomes of interest were: cardiovascular morbidity, defined as myocardial infarction (MI) and cerebrovascular accident (CVA); PAD morbidity, which included ambulation impairment (e.g., as measured by the Walking Impairment Questionnaire¹⁹ [WIQ]), which is measured on a scale of 0–100, or amputation; mortality; health-related quality of life; diagnostic accuracy of the resting ABI (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]); adverse outcomes related to the ABI test; and serious adverse events related to treatment.²⁰ In studies reporting WIQ outcomes, proportions of the population with symptoms at baseline and followup were abstracted and reported.

For treatment KQs (4 and 5), pharmacologic or lifestyle interventions aimed at CVD risk reduction were included. New in this update were exercise and physical therapy interventions aimed at improving lower limb function.

For KQ 1, randomized clinical trials (RCTs), non-randomized controlled intervention studies and systematic reviews that compared screening with the resting ABI to no screening and reported a primary outcome were eligible. For KQ 2, prospectively conducted diagnostic accuracy studies and well-conducted systematic reviews of diagnostic accuracy were eligible. Case-control studies were excluded because selection of participants in this study design has been shown to overestimate sensitivity and result in spectrum bias.^21–25 For KQ 2, diagnostic accuracy studies had to compare the resting ABI with a reference standard (i.e., any diagnostic test that could image the degree of atherosclerosis or degree of impaired blood flow). For KQ 4, any trial or systematic review with at least 12 weeks of followup that compared treatment of PAD with no treatment, with placebo treatment, or with delayed treatment was eligible. For evaluation of harms (KQs 3 and 5), trials, cohort studies, and case-control studies were included; case series or case reports were excluded.

Data Extraction and Quality Assessment

Included studies were critically appraised by 2 independent reviewers using predefined criteria,^26,27 with disagreements resolved by a third reviewer (eTable 2). Articles were rated as good, fair, or poor quality; poor-quality studies were excluded because of substantial concerns about the validity of results for the KQ being addressed. One reviewer abstracted descriptive and outcome data from each study into standardized evidence tables; a second checked for accuracy and completeness.

Data Synthesis and Analysis

Data were synthesized separately for each KQ. The number of contributing studies was not sufficient for quantitative pooling for any KQ, so data are summarized narratively and in tables. For diagnostic accuracy studies (KQ 2), false positive rates (positive test given the absence of the disease [1 – specificity]) and false negative rates (negative test result given the presence of the disease [1 – sensitivity]) were calculated; confidence intervals were calculated using the Agresti-Coull method.²⁸ For treatment trials (KQ 4), standard deviations for continuous outcomes were converted to 95% confidence intervals. For dichotomous outcomes, measures of association and between-group p-values were calculated where not reported with one- and two-sample tests of proportions at the 5% significance level (2-sided test). Calculation methods are described further in the full report.

RESULTS

Five studies (n=5,864) met the inclusion criteria for this review (Figure 2). No direct evidence for PAD screening was identified for KQ 1. One study included in the previous USPSTF systematic review evaluated the diagnostic accuracy of the ABI for KQ 2 and KQ 3.²⁹ Four trials addressed treatment benefits and harms in screen-relevant populations for KQ 4 and KQ 5.^30–33

Benefits of screening

Key Question #1: Is screening for PAD in generally asymptomatic adults with the ABI effective in reducing CVD or PAD morbidity (e.g., impaired ambulation or amputation) or mortality?

No population-based randomized trials of ABI screening alone were identified. Three multicomponent screening trials are in progress, 2 in Denmark (ISRCTN12157806, NCT00662480) and 1 in Spain (NCT03228459), that include PAD screening with the ABI as part of a combined vascular screening program.^34–36 None of these trials test the independent effectiveness of ABI screening.

Accuracy of screening

Key Question #2: What is the diagnostic accuracy of the ABI as a screening test for PAD in generally asymptomatic adults?

Evidence for the diagnostic accuracy of the ABI as a screening test for PAD in asymptomatic adults is limited to one older (2008), fair-quality study that showed low sensitivity and high specificity. This study of 306 older adults in Sweden used whole-body magnetic resonance angiography (MRA) as the reference standard to confirm the presence of PAD.^29,37 The study recruited adults age 70 years at study entry from a random subset of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors cohort study (n=1,016).³⁸ Forty-seven percent of participants were women, 6.9% had a previous MI, 3.9% had a previous CVA, and 10.6% had diabetes. About 8% were current smokers.

The ABI was calculated for each leg by dividing the manual sphygmomanometer readings of posterior tibial artery systolic pressure by the mean of 3 brachial artery systolic pressures. A low ABI was defined as <0.9 and accuracy was calculated based on the whole-body MRA gold standard, with PAD diagnosis defined as ≥50% stenosis.

The prevalence of an ABI <0.9 was 4.5% in the right leg and 4.2% in the left leg (Table 1). The prevalence of MRA-confirmed PAD defined as 50% or greater stenosis was 19.0% and 23.0% in the right and left legs, respectively.

Table 1:

Diagnostic Accuracy of the ABI as a Screening Test for PAD in Generally Asymptomatic Adults (Key Question 2)

Author, Year	No. with ABI <0.9/Total No. (%)	No. with 50% or 100% Stenosis on MRA/Total No. (%)	% Sensitivity (95% CI)	% Specificity (95% CI)	% PPV (95% CI)	% NPV (95% CI)	% FPR (95% CI)	% FNR (95% CI)
Wikstrom, 200829,37 N=306	Right leg 12/268=4.5 Left leg 11/265=4.2	≥ 50% stenosis Right leg 51/268 =19.0 Left leg 61/265= 23.0	Right leg 20 (10 to 34) Left leg 15 (7 to 27)	Right leg 99 (96 to 100) Left leg 99 (96 to 100)	Right leg 83 (51 to 97) Left leg 82 (48 to 97)	Right leg 84 (79 to 88) Left leg 80 (74 to 84)	Right leg 0.9 (0.0 to 3.5) Left leg 1.0 (0.0 to 3.7)	Right leg 80.4 (67.4 to 89.2) Left leg 85.2 (74.0 to 92.3)
		100% stenosis Right leg 34/268 =12.7 Left leg 37/265=14.0	Right leg 24 (11 to 42) Left leg 16 (7 to 33)	Right leg 98 (95 to 99) Left leg 98 (95 to 99)	Right leg 67 (35 to 89) Left leg 55 (25 to 82)	Right leg 90 (85 to 93) Left leg 88 (83 to 91)	Not calculated	Not calculated

Abbreviations: ABI = ankle-brachial index; CI = confidence interval; FNR = false negative rate; FPR= false positive rate; KQ = key question; MRA = magnetic resonance angiography; No. = number; NPV = negative predictive value; PAD = peripheral artery disease; PPV = positive predictive value

Sensitivity was 20% (95% CI, 10–34) and 15% (95% CI, 7–27) in the right and left legs, respectively. Specificity was 99% (95% CI, 96–100) in both limbs. PPV was 83% (95% CI, 51–97) and 82% (95% CI, 48–97) in the right and left legs, respectively. NPV was 84% (95% CI, 79–88) and 80% (95% CI, 74–84) in the right and left legs, respectively.

Harms of screening

Key Question #3: What are the harms of screening for PAD with the ABI?

Evidence for the harms of screening for PAD with the ABI was limited to false positive and false negative rates in the aforementioned diagnostic accuracy study^29,37 (Table 1). The false positive rate was 0.9% (95% CI, 0.0–3.5) and 1.0% (0.0–3.7), and the false negative rate was 80.4% (67.4–89.2) and 85.2% (74.0–92.3) in the right and left legs, respectively. A single participant had a vasovagal attack prior to contrast injection for MRA and was excluded from the study but this adverse event was not due to the ABI. No other harms were reported in this study, nor were there any additional trials examining the downstream harms of screening for PAD with the ABI such as diagnostic testing or procedures.

Benefits of treatment

Key Question #4: Does treatment of screen-detected or generally asymptomatic adults with PAD or an abnormal ABI lead to improved patient health outcomes?

The evidence for treatment of screen-detected or generally asymptomatic adults with an abnormal ABI to improve health outcomes consists of 2 large RCTs of aspirin^30,31 and 2 RCTs of exercise.^32,33

Aspirin

Two good-quality trials (n=4,626), both conducted in Scotland, examined the effectiveness of aspirin in populations with a low ABI.^30,31 The Aspirin for Asymptomatic Atherosclerosis (AAA) trial³¹ (n=3,350) was a placebo-controlled RCT, and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial³⁰ (N=1,276) was a factorial-designed RCT of aspirin and antioxidants versus placebo. Primary outcomes in both trials were composite cardiovascular endpoints; secondary outcomes were fatal and nonfatal MI and CVA, angina, intermittent claudication, transient ischemic attack, and all-cause mortality. Both trials were powered for composite outcomes. Mean followup was 8.2 years in AAA, which was terminated early due to futility, and median followup was 6.7 years in POPADAD.

While both trials recruited asymptomatic populations with no history of CVD, they studied different populations. The AAA trial recruited men and women from the community ages 50 to 75 years with an ABI ≤0.95. The POPADAD trial recruited from diabetes clinics and included men and women ages ≥40 years with an ABI ≤0.99 and diabetes. Mean age was 62.0 and 60.3 years in the 2 trials, respectively. Of the participants, 55.9% and 71.5% were female in the POPADAD and AAA trials, respectively. All participants had diabetes in the POPADAD trial, with a mean HgbA1c of 8.0%, and 2.6% had diabetes in the AAA trial. Nonetheless, ABI values were similar in both trials, with a mean of 0.86 in AAA and a median of 0.90 in POPADAD. In AAA and POPADAD, 33% and 31% were current smokers, respectively. Calculated annual CVD events in the control groups were 0.99% and 2.53% in the AAA and POPADAD trials, respectively, indicating that POPADAD participants had higher baseline CVD risk.³⁹ Statin use was reported in AAA to be 4.2% at baseline and 25% at 5 years of followup.

Intervention groups in both trials received 100 mg of oral aspirin daily; aspirin was enteric coated in AAA. Control groups in both trials received placebo, and the 2×2 factorial-designed POPADAD trial additionally randomized to antioxidant tablet versus placebo. Authors reported no evidence of an interaction between aspirin and antioxidants, so results were analyzed for the group taking aspirin compared to the group not taking aspirin.

Both trials showed no difference between the aspirin and control groups in trial-defined composite cardiovascular outcomes, fatal CVD events, or all-cause mortality (Table 2). The examination of individual CVD outcomes such as MI and CVA likewise showed no statistically significant difference between the aspirin and control groups (eTable 3). There was also no difference in the development of intermittent claudication and need for peripheral arterial revascularization or above-the-ankle amputation procedures (eTable 3). Subgroup credibility ratings did not support a differential treatment effect by age or sex. Within-trial comparisons revealed overlapping confidence intervals, and the single trial—POPADAD—with heterogeneity testing for CVD outcomes by age and sex reported nonstatistically significant interaction testing (eTable 4 and eTable 5).

Table 2.

Composite and Mortality Outcomes for Aspirin in Participants with Low ABI (Key Question 4)

Outcome	Trial Name	Author, Year	No. with the event/Total No. (%)	No. with the event/Total No. (%)	IG vs. CG HR (95% CI)
Primary Composite CVD Outcomea	AAA	Fowkes, 201031	181/1,675 (10.8)	176/1,675 (10.5)	1.00 (0.81 to 1.23)b
	POPADAD	Belch, 200830	116/638 (18.2)	117/638 (18.3)	0.98 (0.76 to 1.26)
Composite Fatal Coronary Events + CVA + CVD Death	AAA	Fowkes, 201031	35/1,675 (2.1)c	30/1,675 (1.8)c	1.17 (0.72 to 1.89)c,d
	POPADAD	Belch, 200830	43/638 (6.7)	35/638 (5.5)	1.23 (0.79 to 1.93)
Composite Nonfatal MI + CVA	AAA	Fowkes, 201031	99/1,675 (5.9)c	106/1,675 (6.3)c	0.93 (0.72 to 1.22) c,d
	POPADAD	Belch, 200830	84 (13.2)c	97 (15.2)c	0.87 (0.66 to 1.14) c,d
All-Cause Mortality	AAA	Fowkes, 201031	176/1,675 (10.5)	186/1,675 (11.1)	0.95 (0.77 to 1.16)
	POPADAD	Belch, 200830	94/638 (14.7)	101/638 (15.8)	0.93 (0.71 to 1.24)

^aDefined in AAA as: initial fatal or nonfatal coronary event or CVA or revascularization; defined in POPADAD as death from CHD or CVA, nonfatal MI or CVA, above ankle amputation for critical limb ischemia

^bHR adjusted for baseline age, ankle-brachial index, cholesterol, systolic blood pressure, smoking, and socioeconomic status; unadjusted HR 1.03 (95% CI, 0.84 to 1.27)

^cCalculated

^dRR

Abbreviations: AAA = Aspirin for Asymptomatic Atherosclerosis Trial; Adj = adjusted; CG = control group; CI = confidence interval; CVA = cerebrovascular accident; CVD = cardiovascular disease; HR = hazard ratio; IG = intervention group; MI = myocardial infarction; N = sample size; No. = number; NR = not reported; POPADAD = Prevention of Progression of Arterial Disease and Diabetes; RR = relative risk

Exercise

Two trials examined the effectiveness of exercise in populations with a low ABI: a good-quality Australian trial by Fowler et al (n=882)³³ and a small, fair-quality US pilot study by Collins and colleagues (n=50).³² The first trial recruited participants from the population-based Western Australian abdominal aortic aneurysm screening trial, while the US pilot RCT included participants with a low ABI, defined as <0.9, and no intermittent claudication who were referred to a Veterans Administration vascular lab. Primary outcomes were the change from baseline to followup at 12³² and 52 weeks³³ in walking ability; this was defined as the ability to walk 100–400 yards before onset of intermittent claudication in the trial by Fowler et al and the WIQ walking distance score in the Collins trial. Because it was designed as a small, short-term feasibility study, the Collins trial was not powered for its primary outcome.

Compared to the populations in the aspirin trials, participants in the exercise trials were more frequently men, older, more symptomatic, and had a lower ABI. Both trials were exclusively or almost exclusively conducted among men. Mean age was 73.1 years in the trial by Fowler et al and 69.1 years in the Collins trial. Because the trial by Fowler et al recruited participants who screened positive for PAD via either the ABI or the Edinburgh Claudication Questionnaire, about 44% of the population had intermittent claudication; atypical symptoms were present in about 9% of the population and the remainder were asymptomatic. Fifty-six percent of participants in the Collins trial were asymptomatic for PAD and the remaining 44% had atypical symptoms. Mean ABI was 0.79 in the trial by Fowler et al and 0.74 in the Collins trial.

The interventions in the 2 trials were somewhat heterogeneous with respect to format and intensity; each trial included lifestyle messages in addition to exercise. Intervention details are provided in eTable 6. The intervention in the trial by Fowler et al included a smoking cessation intervention and physical therapy (PT) referral. The 52-week intervention began with an individual face-to-face session including explanation of the PAD screening test results and provision of an educational packet about PAD, a brochure about the community PT service, smoking cessation information if applicable, and a copy of the letter sent to their general practitioner. The community PT service goal was to increase physical activity and included weekly 45-minute supervised sessions for 49 sessions or an individually designed, home-based physical activity program. In addition, all men were advised to walk for 30 minutes or more each day. In the control group, nurses disclosed results of diminished flow to the lower extremities but stated “there is presently no evidence to suggest you do anything about it at this time.” The intervention in the Collins trial included 2 components delivered individually by a nurse: risk factor modification and counseling to improve physical activity. The 12-week intervention started with a face-to-face session followed by 5 phone visits, each lasting less than 30 minutes. The control group was advised to continue routine care with their primary care physician. Adherence to the physical activity component differed widely between the 2 trials: it was relatively low in the longer trial by Fowler et al (16.5% at 1 year of followup) and high in the 12-week Collins trial related to the physical activity recommendation of 30 minutes 3 times per week (40% at baseline and 82% by the final phone call).

The variability of outcome measures reported in the 2 trials precludes definitive conclusions, but generally, evidence suggests that exercise-based treatment of screen-detected PAD may have limited effectiveness. Neither trial showed statistically significant between-group differences in self-reported quality of life, as measured by the Medical Outcomes Study Short-Form Health Survey (MOS SF-36), used in the Collins trial, or the Rosser Health-related Quality of Life instrument, used in the trial by Fowler et al. Only the Collins trial reported eligible ambulation impairment outcomes, showing no difference in the primary outcome of mean walking distance score on the WIQ or walking speed. However, a statistically significant larger improvement was found for the intervention group for the stair-climbing component of the WIQ compared to the control group (mean difference 15.1 [95% CI, 2.4 to 32.6]; P = .02). Neither trial showed statistically significant between-group differences for the proportion of participants experiencing symptoms between baseline and followup. However, in the trial by Fowler et al, the proportion of participants experiencing atypical symptoms and intermittent claudication decreased in both the intervention and control groups. Symptom patterns in the Collins trial were more inconsistent, possibly due to a very small sample.

Harms of treatment

Key Question #5: What are the harms of treatment of screen-detected or generally asymptomatic adults with PAD or an abnormal ABI?

Evidence for the harms of treatment are limited to the 2 trials of aspirin and suggest that aspirin may be associated with increased major bleeding, although rare events and wide confidence intervals preclude definitive conclusions from these studies alone. Both AAA and POPADAD report bleeding harms associated with 100 mg daily aspirin use. Major gastrointestinal (GI) bleeding requiring hospital admission was similar in the aspirin and control groups (0.5% vs 0.5%; relative risk (RR) 1.13 [95% CI, 0.44–2.91]).³¹ Major hemorrhage (defined as nonfatal or fatal hemorrhagic CVA, fatal or nonfatal subarachnoid/subdural hemorrhage, GI bleed requiring admission, and other bleeding requiring hospital admission) in AAA was higher in the aspirin group but did not reach statistical significance (2.0% vs 1.2%; HR 1.71 [95% CI, 0.99–2.97]).³¹ Five hemorrhagic CVAs occurred in the aspirin group and 4 occurred in the control group; confidence intervals were wide due to the rare event rate (0.3% vs 0.2%; RR 1.25 [95% CI, 0.34–4.65]). POPADAD reported a nonsignificant reduction in fatal hemorrhagic CVA in the aspirin group, but again, confidence intervals were wide due to rare events (2 events [0.3%] vs 3 events [0.5%]; RR 0.67 [95% CI, 0.11–3.98]).

DISCUSSION

An overall summary of the evidence is presented in Table 3. No population-based screening trials address the effectiveness of ABI screening for PAD as a single intervention to reduce PAD- or CVD-related morbidity or mortality. The indirect chain of evidence linking screening with the ABI in generally asymptomatic adults to improved health outcomes is limited (Figure 1). A single diagnostic accuracy study demonstrates that the ABI has poor sensitivity for detecting PAD in unselected populations; this is the same study that was included in the previous review for the USPSTF. Evidence for treatment benefit consists of 2 trials of aspirin and 2 trials of exercise; 1 of these aspirin trials³⁰ and both exercise trials^32,33 are newly included in this updated review for the USPSTF. The 2 aspirin trials demonstrated that aspirin is not effective in reducing composite CVD morbidity or mortality over 6–8 years of followup and an increased bleeding risk that was not statistically significant. However, both trials defined low ABI with higher thresholds than used in clinical practice because their aim was to use the ABI as a nontraditional risk factor to identify a high CVD risk population that might benefit from aspirin, not to screen for clinical PAD; as such, a sizable proportion of the study population would not have met the clinical threshold of <0.9. The 2 exercise trials similarly showed limited effectiveness across most outcome measures; statistically significant improvement was seen for the stair-climbing component of the WIQ only, reported in 1 trial.

Table 3.

Summary of Evidence by Key Question

Number of Studies and Design, No. of Participants Randomized (n)	Outcome	Number of Trials (k), Number of Participants Analyzed (n)	Summary of Findings by Outcome	Consistency and Precision	Reporting Bias	Study Quality	Body of Evidence Limitations	Applicability
KQ 1: Is screening for PAD in generally asymptomatic adults with the ABI effective in reducing CVD or PAD morbidity (e.g., impaired ambulation or amputation) or mortality?
0 studies	Morbidity or mortality	0	NA	NA	NA	NA	NA	NA
KQ 2: What is the diagnostic accuracy of the ABI as a screening test for PAD in generally asymptomatic adults?
1 prospective diagnostic accuracy study, n=307 (0/1 trials identified in update)	Sensitivity, specificity, PPV, NPV	k=1, n=306	ABI has low sensitivity (7–34%) and high specificity (96–100%) compared to MRA gold standard imaging.	Consistency-NA (single study) Imprecise	Not detected	1 Fair	Single study, not clear if MRA interpreters were blind to ABI results; harms (aside from FP and FN) not reported other than single vasovagal episode	Screening population of older adults (age 70) in Sweden. The low sensitivity reported in this single study is well below the sensitivities reported in symptomatic populations.
KQ 3: What are the harms of screening for PAD with the ABI?
1 prospective diagnostic accuracy study, n=307 (0/1 trials identified in update)	Harms	k=1, n=306	ABI has a high false negative rate (>80%) reflecting the low sensitivity in screening for PAD.	Consistency-NA (single study) Imprecise	Not detected	1 Fair
KQ 4: Does treatment of screen-detected or generally asymptomatic adults with PAD or an abnormal ABI lead to improved patient health outcomes?
Aspirin 2 RCTs, n=4,626 (1/2 trials identified in update)	CVD composite, ACM, individual CVD outcomes	k=2, n=4,626	Aspirin 100 mg daily showed no effect on CVD composite events in the two trials: Adj HR (95% CI): 1.00 (0.81 to 1.23) HR (95% CI): 0.98 (0.76 to 1.26) No effect on ACM: HR (95% CI): 0.95 (0.77 to 1.16) HR (95% CI): 0.93 (0.71 to 1.24) No statistically significant difference in individual CVD outcomes including: MI, CVA, development of intermittent claudication and need for peripheral arterial revascularization or above the ankle amputation procedures	Reasonably consistent Imprecise	Not detected	2 Good	Studies designed to detect differences in CVD composites but not individual CVD outcomes.	Two Scottish trials in asymptomatic patients with low ABI defined as ≤0.95 and ≤0.99 (thresholds not typically used to define abnormal ABI in clinical practice). One trial exclusively in patients with diabetes. Populations at intermediate to high CVD risk.
Exercise 2 RCTs, n=932 (2/2 trials identified in update)	Quality of Life	k=2, n=745	No difference in quality of life changes from baseline (as measured by MOS SF-36 and Rosser HrQOL questionnaire)	Reasonably consistent Imprecise	Not detected	1 Good, 1 Fair	One feasibility trial in almost exclusively men was short (12 weeks) and underpowered (n=50) to detect difference in primary or secondary outcomes. Second trial (N=882) powered to detect walking ability before onset of symptoms	Unclear whether population representative of screen-detected population; included participants almost 100% male
	WIQ	k=1; n=48	No difference in WIQ score change from baseline for distance or speed components; statistically significant improvement in stair climbing component in IG compared to CG	NA	Not detected	1 Fair
	Proportion of participants with symptoms	k=2, n=722	No change in proportion of participants who develop IC or atypical symptoms	Reasonably consistent Imprecise	Not detected	1 Good, 1 Fair
KQ 4a: Does the effectiveness of treatment vary by subpopulations at greater risk for PAD?
Aspirin 2 RCTs, n=4,626 (1/2 trials identified in update)	CVD composite, individual CVD outcomes, fatal CVD events, ACM	k=2, n=4,626	No compelling evidence to support a differential treatment effect by age, sex, or diabetes status. Within trial comparisons revealed overlapping CIs and the single trial (POPADAD) reporting heterogeneity testing for CVD outcomes by age and sex reported nonstatistically significant interaction testing. Results exclusively in participants with diabetes (POPADAD) showing similar outcomes to those almost exclusively without diabetes (AAA).	Inconsistent (age) Reasonably consistent (sex) Imprecise (age, sex)	Not detected	2 Good	Only 1 trial performed interaction testing by age, sex and unclear if a priori planned analysis. Other trial prespecified subgroup analysis but did not perform interaction testing. No available data for within-group comparisons by diabetes status. CIs wide and overlapping across subgroups analyzed.	Both Scottish trials in asymptomatic patients with low ABI defined as ≤0.95 and ≤0.99 (thresholds not typically used to define abnormal ABI in clinical practice). One trial exclusively in patients with diabetes. Populations at intermediate to high CVD risk.
Exercise 0 studies	NA	NA	No exercise trials examine the differential treatment effect by subpopulation.	NA	NA	NA	NA	NA
KQ 5: What are the harms of treatment of screen-detected or generally asymptomatic adults with PAD or an abnormal ABI?
Aspirin 2 RCTs, n=4,626 (1/2 trials identified in update)	Major GI bleeding requiring admission	k=1, n=3,350	Major GI bleeding requiring hospital admission was similar in one reporting trial (AAA) of 100 mg enteric coated aspirin at 8.2 years of followup: 0.5% versus 0.5%; RR (95% CI): 1.13 (0.44 to 2.91)). Limited evidence from this trial demonstrates a higher risk for major bleeding events with the use of aspirin, but this was not statistically significant. Two trials reported conflicting results on total or fatal hemorrhagic CVA risk with wide confidence intervals due to rare event rate.	Consistency-NA (single study) Imprecise	Not detected	1 Good	Rare events, wide CIs	Asymptomatic patients with low ABI defined as ≤0.95 with intermediate CVD risk
	Major hemorrhage (defined as nonfatal or fatal hemorrhagic CVA, fatal or nonfatal subarachnoid/subdural hemorrhage, GI bleed requiring admission, and other bleeding requiring hospital admission)	K=1, n=3,350	Major hemorrhage did not reach statistical significance but was slightly higher in the aspirin group: 2.0% versus 1.2%; HR (95% CI): 1.71 (0.99 to 2.97).	Consistency-NA (single study) Imprecise	Not detected	1 Good	Single trial, relatively rare event with wide CIs
	Hemorrhagic CVA	k=2, n=4,626	Nonsignificant higher risk for total hemorrhagic CVA with aspirin in AAA (0.3% v 0.2%; RR 1.25 (95% CI, 0.34 to 4.65) and a lower risk for fatal hemorrhagic CVA in POPADAD (0.3% versus 0.5%; RR 0.67 [95% CI, 0.11 to 3.98]) but CIs were wide due to rare events.	Inconsistent, Imprecise	Not detected	2 Good	Somewhat conflicting results when comparing total and fatal hemorrhagic across 2 trials which recruited different populations (with and without diabetes)
Exercise 0 studies	NA	No trials reporting harms	NA	NA	NA	NA	NA	NA

Abbreviations: AAA = Aspirin for Asymptomatic Atherosclerosis Trial; ACM = all-cause mortality; Adj = adjusted; CG = control group; CI = confidence interval; CVA = cerebrovascular accident; CVD = cardiovascular disease; EPC = Evidence-based Practice Center; GI = gastrointestinal; HR = hazard ratio; IG = intervention group; KQ = key question; MI = myocardial infarction; NA = not applicable; NPV: negative predictive value; PPV = positive predictive value; POPADAD = Prevention of Progression of Arterial Disease and Diabetes; RR = relative risk

The poor sensitivity of the ABI identified in the 1 included diagnostic accuracy study contrasts with evidence in symptomatic populations. Other systematic reviews of largely symptomatic populations have reported much higher diagnostic accuracy.^9–11,17 For example, pooled sensitivities and specificities for ABI ≤0.9 compared to an angiographic reference standard have been reported at 75% (95% CI, 71–79) and 86% (95% CI, 83–90), respectively, with significant heterogeneity.¹⁷ The far lower sensitivity and higher specificity in the single included study compared to the larger literature involving symptomatic populations is likely due to a combination of factors: an expected poorer accuracy in screening populations compared to symptomatic populations (spectrum effect);⁴⁰ different methods for calculating the ABI; and limitations of study quality in a single, small population sample. One recent diagnostic accuracy study not meeting the review’s inclusion criteria reported a sensitivity of 49% and specificity of 94% for targeted screening in high-risk populations as defined per AHA guidelines⁵ (>65 years or >50 years with the presence of diabetes or currently smoking, or patients with exertional leg pain) using color duplex as the reference standard.⁴¹

Similarly, the finding of limited effectiveness of exercise interventions in the present review differ from the findings of several systematic reviews in largely symptomatic populations. The literature centered on symptomatic populations has concluded that exercise programs are associated with improved maximum walking distance and time, pain-free walking distance, 6-minute walk, WIQ scores, and quality of life.^9,12–14 Expecting unselected populations to achieve improvements in ambulation may not be reasonable if they are not reporting symptoms; however, if patients are unaware of symptoms because they have limited their activity levels, treatment could potentially improve ambulation and quality of life. Several observational studies of screen-detected or asymptomatic populations do show that those with a low ABI have statistically significant worse measures of function than those with a normal ABI, including 6-minute walk distance, 4-meter walking velocity, 400-meter walk time, SF-36 physical functioning subscale scores, and WIQ distance and speed scores.^42–47 Two exercise-based intervention trials in patients with PAD or a low ABI that were not included in this review have shown improved lower-extremity functional outcomes but were not included because the baseline ABIs and WIQ distance and speed scores reflect a more severe functional impairment and disease severity than would be expected in an unselected screen-detected primary care population.^48,49 Replication of these findings in screened populations is needed.

Other systematic reviews of antiplatelet therapy have similarly reported no overall reduction in CVD events with aspirin compared to control in populations with a low ABI.^9,15,16 Findings of bleeding risk associated with aspirin use should be considered in the context of the broader literature about aspirin use for CVD primary prevention.⁵⁰ The present review did not identify any other pharmacologic trials in screen-detected PAD populations reporting patient health outcomes. Observational studies suggest both functional and mortality benefits of statins.^9,51–54 An RCT of statin therapy in individuals with an abnormal ABI may be of uncertain value because many such participants may qualify for statin therapy based on 10-year risk alone—data from a large 2008 individual participant data meta-analysis suggest that 95% of men with an ABI ≤0.9 would already be above a 10% Framingham Risk Score 10-year risk threshold and 41% of women would be above this threshold.¹

Some organizations recommend screening for PAD with the ABI in populations above certain ages or with various risk factors (Table 4).^5,55–58 The rationale is that high-prevalence populations, such as those at older age, with diabetes, and who smoke cigarettes, can be easily identified based on established risk factors for PAD;⁵⁹ that the ABI is relatively accurate based on studies in symptomatic patients; and that cardiovascular risk factor modification is appropriate because CVD morbidity and mortality are high in adults with PAD regardless of symptoms.⁵⁵ Conversely, even when higher-prevalence populations with high CVD risk are identified for screening, the missing link in the indirect evidence chain remains the effectiveness of screening in identifying individuals who are not already candidates for lifestyle and pharmacologic treatment based on their global CVD risk.⁶⁰

Table 4.

Recommendations for Screening for PAD with ABI in Individuals Without History or Physical Examination Findings Suggestive of PAD

	USPSTF2018	ESC 201769	AHA/ACC 20165	SVS 201555	AAFP 201356	NICE 201257	ACPM 201158
Population for which screening is recommended	Insufficient evidence for asymptomatic adults	Aged >65 y; Aged <65 y classified at high CVD risk according to ESC guidelines; aged >50 y with family history; known atherosclerotic disease (CAD, any PAD), AAA, CKD, heart failure	Aged ≥65 y; Age 50–64 y with risk factors for atherosclerosis (e.g., DM, history of smoking, hyperlipidemia, hypertension) or family history of PAD; Age <50 y with DM and 1 other risk factor for atherosclerosis; known atherosclerotic disease in another vascular bed (e.g., coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA)	Aged >70 y, smokers, DM; abnormal pulse examination; or other established CVD	Aged >65 y; ≥50y with history of DM, smoking, exertional leg pain, or a non-healing extremity wound	Adults with symptoms suggestive of PAD or DM, non-healing wounds on legs or feet or unexplained leg pain or considered for interventions to the leg or foot or need to use compression hosiery	Clinicians should be alert to symptoms in those at increased risk (>50 y, smokers, and DM) and evaluate patients with clinical evidence of vascular disease
Recommendation Grade or Evidence Rating	Ia	NR	Class IIa, B-NRb	2; Cc	Cd	Opinion	NR

^aI statement is insufficient to assess the balance of benefits and harms of service

^bClass of recommendation: Class IIa indicates moderate benefit where benefit >>risk (moderate strength) and level B quality of evidence (nonrandomized designs)

^cDefined as weak recommendation based on low-quality or very-low-quality evidence

^dBasis for recommendation is consensus, disease-oriented evidence, usual practice, expert opinion or case series. Disease-oriented evidence is defined as measures of intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes.

Abbreviations: AAA = abdominal aortic aneurysm; ABI = ankle brachial index; ACMP = American College of Preventive Medicine; AHA/ACC = American Heart Association and American College of Cardiology; AAFP = American Academy of Family Physicians; CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; ESC = European Society of Cardiology; NR = not reported; SVS = Society for Vascular Surgery; USPSTF = United States Preventive Services Task Force; y = year(s)

Three population-based screening trials are testing the effectiveness of combined multiple vascular screening tests on all-cause mortality and/or cardiovascular morbidity and mortality at 10–15 years of followup. However, none of these trials isolates the independent effectiveness of ABI screening. The Viborg Vascular (VIVA) Screening Trial enrolled 50,156 men ages 65 to 74 years and randomized to screening versus no screening for hypertension, PAD and abdominal aortic aneurysm; the intervention included subsequent counseling for physical activity, smoking cessation, and a low-fat diet, as well as cholesterol testing with aspirin and statin therapy prescribed to those meeting a total cholesterol threshold value.⁶¹ An interim analysis at median 4.4 years of followup reported a 0.006 absolute risk reduction (95% CI, 0.001–0.011) in all-cause mortality in the screened group (HR 0.93 [95% CI, 0.88–0.98]) and a reduction in PAD-specific hospital days (HR 0.81 [95% CI, 0.76–0.87]) Authors hypothesized that the all-cause mortality benefit was largely seen from preventive measures including statin and aspirin use; these conclusions were based on sensitivity analyses that removed smokers or those initiating hypertensive therapy, which did not change the main results. Applicability of such findings in the context of current treatment thresholds for pharmacotherapy based on global CVD risk^62–64is uncertain as nearly all participants would have ≥10% 10-year CVD risk based on age and male sex alone,⁶⁵ thus would already be candidates for consideration of statins or aspirin. Secondary analyses including cost-effectiveness analyses to estimate the independent effect of ABI screening are planned, but it is unlikely that such analyses will definitively demonstrate ABI screening effectiveness given the aforementioned considerations. Two other large, in-progress multicomponent screening trials using population-based or primary care-based recruitment include the ABI as part of the multicomponent screening intervention and will report primary outcomes of all-cause mortality and CVD events at 10 years of followup.^35,36,66 As with the VIVA trial, the multicomponent nature of these trials will likely preclude definitive conclusions about the effect of ABI screening alone.

Limitations

This evidence report has several limitations. To be consistent with the scope of the USPSTF, the review excluded symptomatic individuals for both diagnostic accuracy and treatment questions. However, the varied clinical presentation of PAD and the recognition that severity of leg symptoms may not directly correspond to atherosclerotic burden are problematic in identifying a screening-relevant population. The scope of this review did not include diagnostic accuracy of other screening methods or modalities such as automated oscillometric ABI measurement methods;^67,68 the post-exercise ABI, which may be relevant in clinically “asymptomatic” populations who self-limit exertion; and the toe-brachial index.

For treatment trials, the narrow population requirement could be considered unnecessarily limiting. However, in order to develop an indirect chain of evidence in support of screening, it is critical that treatment trials be applicable to a population that reflects the screen-detected population in terms of disease severity and treatment effectiveness. The prespecified. health outcomes required in this review include CVD and PAD morbidity or mortality or quality of life with the exclusion of intermediate outcomes such as behavior changes, ABI changes, intermediate cardiovascular risk factors, or intermediate measures of lower limb function to include the 6-minute walk test or lower-extremity strength. No treatment trials were excluded from this review on the basis of reporting 6-minute walk outcomes.

Conclusions

There was no direct evidence and limited indirect evidence on the benefits of PAD screening with the ABI in unselected or asymptomatic populations. Available studies suggest low sensitivity and lack of beneficial effect on health outcomes, but these studies have important limitations.