Final Research Plan
Peripheral Artery Disease and Cardiovascular Disease: Screening and Risk Assessment With the Ankle-Brachial Index
June 16, 2016
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
This systematic review will examine the evidence on the effectiveness of screening in generally asymptomatic populations for peripheral artery disease (PAD) in order to improve cardiovascular and PAD-specific morbidity and mortality. A concurrent systematic review on the use of nontraditional risk factors in cardiovascular disease (CVD) risk assessment will address the evidence on the effects of resting ankle brachial index (ABI) on 1) the discrimination or calibration of multivariate risk prediction models when used in addition to traditional CVD risk factors, 2) CVD risk reclassification, and 3) CVD health outcomes. Together, these two systematic reviews will serve as the basis for the USPSTF recommendation on screening for PAD.
Abbreviation: ABI=ankle brachial index.
Figure 1 is the analytic framework that depicts the five Key Questions (KQs) to be addressed in the systematic review. The figure illustrates how screening generally asymptomatic adults for peripheral artery disease (PAD) with the ankle brachial index (ABI) may reduce mortality, cardiovascular morbidity, PAD morbidity, and quality of life (KQ 1). The figure also depicts the diagnostic accuracy of ABI as a screening test for PAD (KQ 2) and the harms of screening (KQ 3). KQ 4 depicts whether treatment of screen-detected or generally asymptomatic adults with PAD or abnormal ABI improves the patient health outcomes evaluated in KQ 1 and if there are harms associated with treatment (KQ 5).
- 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?
- Does the effectiveness of screening for PAD vary by subpopulations at greater risk for PAD?
- What is the diagnostic accuracy of the ABI as a screening test for PAD in generally asymptomatic adults*?
- Does the diagnostic accuracy of screening with the ABI vary by subpopulations at greater risk for PAD?
- What are the harms of screening for PAD with the ABI?
- Do the harms of screening for PAD vary by subpopulations at greater risk for PAD?
- Does treatment of screen-detected or generally asymptomatic adults* with PAD or an abnormal ABI† lead to improved patient health outcomes?
- Does the effectiveness of treatment vary by subpopulations at greater risk for PAD?
- What are the harms of treatment of screen-detected or generally asymptomatic adults* with PAD or an abnormal ABI†?
- Do the harms of treatment vary by subpopulations at greater risk for PAD?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- In primary care, what proportion of adults with an abnormal ABI† are generally asymptomatic*?
- What proportion of generally asymptomatic adults* with an abnormal ABI receive additional diagnostic testing?
- What proportion of generally asymptomatic adults* with an abnormal ABI have an ABI greater than 1.40?
- What proportion of generally asymptomatic adults* with an ABI greater than 1.40 have PAD?
- What proportion of generally asymptomatic adults* with PAD or an abnormal ABI† have lower extremity functional impairment? What is the degree of lower extremity functional impairment, and how does it compare to impairment in patients with reported symptoms (e.g., claudication)?
- Do generally asymptomatic adults* with PAD or an abnormal ABI† have the same risk of global CVD events as symptomatic adults with PAD?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).
|Population||KQs 1–3: Unselected or community-dwelling, generally asymptomatic adults*
KQs 4, 5: Screen-detected or generally asymptomatic adults with PAD or an abnormal ABI†
A priori subpopulations at greater risk for PAD will be examined based on the following factors: age (particularly ≥65 years), sex, race/ethnicity, diabetes, smoking, and hypertension status
|Symptomatic adults; study populations consisting exclusively of adults with known CVD or severe chronic kidney disease (stages 4 and 5)|
|Setting||Primary care and outpatient settings (i.e., ambulatory care)||Vascular surgery clinics (KQs 1, 2); hospital/inpatient settings|
|Disease/Condition||Lower extremity PAD secondary to atherosclerosis‡||Other anatomic locations for vascular disease (e.g., coronary artery stenosis, abdominal aortic aneurysm)|
|Screening||Resting ABI||History taking, physical examination, questionnaires, digital subtraction arteriography (DSA), duplex ultrasonography, magnetic resonance angiography (MRA), computed tomographic angiography (CTA), toe pressure measurement, treadmill testing (exercise ABI), pulse oximetry, near-infrared spectroscopy, and all invasive diagnostic testing|
|Treatment or management interventions||
|Comparisons||KQ 1: No screening
KQ 2: Reference standard (DSA, diagnostic imaging of atherosclerosis [e.g., MRA, CTA]) or degree of impaired blood flow (e.g., duplex ultrasonography)
KQ 4: True control group (receives placebo, no intervention, or usual care); intervention/treatment at later or symptomatic stage of disease (vs. earlier or asymptomatic stage)
|Outcomes||KQ 1: Cardiovascular morbidity (myocardial infarction, cerebral vascular accident), PAD morbidity (ambulation impairment, amputation), or mortality (all-cause, PAD-related, or CVD-related); health-related quality of life
KQ 2: Sensitivity, specificity, positive and negative predictive value for PAD, and incidence or prevalence
KQ 4: Patient health outcomes (listed above for KQ 1)
|Harms||KQ 3: Adverse outcomes related to ABI test (diagnostic inaccuracy) or harms of subsequent testing
KQ 5: Serious adverse events (e.g., death, serious adverse drug reaction) or unexpected medical attention (e.g., emergency department visit, hospitalization)
|Study designs||KQs 1, 4: Good-quality systematic reviews and randomized or clinically controlled trials
KQ 2: Good-quality systematic reviews and diagnostic accuracy studies
KQs 3, 5: Good-quality systematic reviews, randomized or clinically controlled trials, and cohort or case-control studies
|Poor-quality studies based on established design-specific quality criteria
KQ 2: Case-control studies of diagnostic accuracy
KQ 4: Studies with less than 3 months of followup
|Countries||Economically developed countries, defined as member countries of the Organisation for Economic Co-operation and Development (2015): Australia, Austria, Belgium, Canada, Chile, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom, and United States||
|Language||English only||Non-English languages|
* Adults without lower extremity symptoms or with vague symptoms not attributed to PAD.
† Defined as an ABI of ≤0.90 or >1.40.
‡ The condition definition for PAD would ideally be confirmed by diagnostic imaging (MRA, CTA, or DSA); however, the review will include trials that recruit participants with an abnormal ABI.
A draft research plan was posted on the USPSTF Web site for public comment from March 24 to April 20, 2016. This review will address screening in unselected populations according to USPSTF methodology but will also review the evidence for subpopulations at greater risk for PAD based on age (particularly ≥65 years), sex, race/ethnicity, diabetes, smoking, and hypertension status. Based on the comments it received, the USPSTF revised the eligibility criteria to also include studies in adults with diabetes. Adults with known coronary artery disease or severe chronic kidney disease will continue to be excluded because their high risk places them outside of the screening paradigm. Comments suggested that two points could benefit from additional clarification. First, the addition of “generally asymptomatic adults” as well as “screen-detected adults” to KQs 4 and 5 (treatment effectiveness and harms) is intended to expand rather than restrict the number of eligible trials. Second, all of the PAD morbidity outcomes (e.g., impaired ambulation or amputation) and CVD outcomes for KQ 1 will be analyzed and reported individually, not as part of a single composite outcome.